DNA methylation profiles of ovarian cysts resemble ovarian tissues, but not endometrial tissues

DNA methylation profiles of ovarian cysts resemble ovarian tissues, but not endometrial tissues | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article DNA methylation profiles of ovarian cysts resemble ovarian tissues, but not endometrial tissues Xiaohui Zhang, Xiaojing Zhao, Jiapo Wang, Zhang Yifang, Jinhong Chen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3446301/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Despite the high prevalence of ovarian cyst, its origin is still under debate. Prevailing retrograde menstruation model predicts that ectopic endometrial cells migrate and develop into ovarian cysts. However, other models were also proposed. Because DNA methylation states exhibit a tissue specific pattern, we profiled the DNA methylation for ovarian cysts and paired eutopic endometrial and ovarian tissues from four patients. Surprisingly, DNA methylation profiles showed the ovarian cysts were closely grouped with normal ovarian but not endometrial tissues. These results suggested alterative origin of ovarian cysts or strong epigenetic reprogramming of infiltrating endometrial cells after seeding the ovarian tissue. Ovarian endometriosis DNA methylation tissue of origin Figures Figure 1 Background Ovarian endometriosis has a high prevalence and affects millions of women worldwide. The origin of endometriosis is still puzzling. It is generally considered to be derived from endometrium[ 1 ], however, other hypotheses were also provided. For instance, a latest report suggested that ~ 60% of endometriosis may originate from fallopian tube[ 2 ].Ovarian origin recently, researchers found and confirmed the existence of cells expressing two germ cell line specific proteins (deadboxpolypeptide4/interferoninducedtrans, membraneprotein3, ddx4/ifitm3) in ectopic ovarian EMS lesions, suggesting that ovary-originated stem cell may contribute to the occurrence and progression of ovary EMS lesions [ 3 ]. To answer this question, we resorted to paired DNA methylation assay for ovarian endometriosis, normal ovarian and endometrial tissues in a small pilot cohort. Epigenetic modifications regulate the transcriptional process, and abnormalities lead to various diseases. Among the most investigated and vital modifications, DNA methylation was linked to alterations in endometrial function/dysfunction-related genes, modulating cell proliferation, inflammation/immune response, angiogenesis, and steroid hormone response. These findings offer a deep understanding of epigenetic reprogramming and steroid hormone effects in endometrium aiding in the pathogenesis and pathophysiology of endometriosis [ 4 – 6 ]. Previous reports have shown that the endometriosis pathophysiology involves aberrant promoter methylation of several genes, for instance, HOXA10 [ 7 ], steroidogenic factor 1 [ 8 ] and aromatase [ 9 ]. As a new research area, genome-wide DNA methylation analysis can clarify the relationship between DNA methylation state and endometriosis. Our study utilized a microarray-based approach to determine the accurate DNA methylation level. The abnormal methylation expression between ovarian endometriosis cells, eutopic endometrium and ovarian tissues was analyzed. Methods Sample Collection. Endometrium was biopsied from 4 fertile women receiving surgery for histologically confirmed unilocular/multilocular ovarian endometriosis (2:2). Normal ovarian tissue and eutopic endometrium of the same patient were used as controls. Specimens were obtained from subjects without hormone-based treatments at least 1 quarter before specimen acquisition and menstruation just clean, that is, endometrial hyperplasia. Upon surgical dissection, partial tissue was cryopreserved for microarray analyses. Endometrium and cysts were rinsed by Dulbecco's modified eagle's medium (DMEM) comprising of glutamine, 50mg/ml streptomycin, and 50iu/ml penicillin (all from Invitrogen, Paisley, UK), and subsequently cut to a size of 1mm 3 . Then, ESC was isolated via screening with 70mm nylon mesh after 2 hours of collagenase (Sigma, Mo, USA) procession in a shaking incubator at 37℃. The filtrate was washed three times. The human investigation committee of Tongji University endorsed the research. DNA methylation analysis Illumina 850k methylation EPIC Bead Array data was processed through a standard pipeline using the ChAMP package in R. The ChAMP can load raw intensity data in the form of IDAT or matrix containing methylation value (beta) of each probe[ 10 ]. After filtering and normalization, the 12 samples were combined into an array including only overlapping CpG sites and finally 743,800 probes were included. Principal component analysis (PCA) was firstly run on normalized methylation data to evaluate the similarity of methylation profile in 12 samples. Bumphunter method was implemented to identify differentially methylated regions (DMR) within ChAMP (ChAMP.DMR function). The methylation beta value of each DMR was calculated using the mean value of all the probes that included in each DMR. The heatmap was drawn using all the DMRs within 12 samples. The Family-wise error rate (FWER) adjusted p-value < 0.05 was considered a statistical significance threshold. Therefore, the DMR regions with a FWER < 0.05 was considered as significantly differentially methylated regions. The genomic regions for significantly differentially methylated regions were annotated with the definition of TSS3000 (3000 upstream and downstream of transcription initiation locus respectively) as the promoter region. Results DNA methylation profiles showed the ovarian cysts were closely grouped with normal ovarian but not endometrial tissues. Total of 12 samples from 4 patients, each with endometriosis, ovarian and endometrial tissues were profiled with illumina 850k methylation array. Principal component analysis clearly showed that endometriosis samples were tightly clustered with samples of ovarian tissue (Fig. 1 A). One of endometrial sample was located further away from other samples as an outlier, and this sample also showed a slightly different normalized beta distribution compared with other samples (Fig. 1 B). Therefore, we removed this sample for the downstream analyses. To confirm this result, we also performed PCA on our samples as well as publically available DNA methylation data on healthy endometrial biopsies[ 11 ], and as expected, healthy endometrial samples from public data were closer to our endometrial samples (Fig. 1 C). Abnormal epigenetic profiles of genes involving receptors, signaling pathways and immune responses Most of previous studies compared the endometriosis with endometrial tissues; therefore we analyzed differential DNA methylation between endometriosis and endometrial tissues and identified the differentially methylated regions (TableS1). In comparison with eutopic endometriosis, many genes in ovarian endometrial cysts (choESC) had different degrees of methylation, high and low (Table 1 , Table 2 ),With acquired methylation profiles data, we identified the detailed features of aberrantly methylated genes in choESC using gene cards (the humor gene database) analyses. Depending on pathway analysis of screened genes, there are abnormalities of relevant signal transduction pathways involving endometriosis onset and progression, developmental processes, human early embryonic development, regulation of caspase, tyrosine, and mRNA metabolic processes et al. It indicated an abnormal expression pattern of choESC in peritoneal environment. As analyzed by GO and KEGG, the genes were primarily engaged in epithelial-mesenchymal transition(EMT), adhesion integrity, apoptosis, proliferation, and cell differentiation, et.al. Table 1 Hypomethylation in endometrial tissues compared the endometriosis. Gene Symbol Gene name Fold Change Ratio(Endometrial vs Cyst) P value Function HOXB1 homeotic genes B1 3.749 0 Important growth and development regulatory genes regulator of retinoic acid response elements (RAREs) MCC membrane compartment of Can1 3.709 0 one cytoplasm membrane microdomain regulating metabolism, cellular morphogenesis, signaling cascades, and mRNA degradation. TMEM101 transmembrane protein 101 3.695 0 upregulation and increase the expression of NF-κB in ovary cancer. CASS4 Homo sapiens Cas scaffolding protein family member 4 3.624 0.004 Possible docking protein which may play a role for tyrosine-kinase-based signaling related to cell adhesion. Regulates FAK activity, focal adhesion integrity, and cell spreading. BST2 bone marrow stromal cell antigen 2 3.612 0 Regulating Type-I interferon and interleukin-6 generation FABP3 Fatty Acid Binding Protein 3 3.150 0.004 During the early stages of pregnancy, upregulating cell growth and proliferation in uterine endometrium FAIM2 Fas Apoptotic Inhibitory Molecule 3.052 0.012 specifically protecting cells from Fas-induced apoptosis SHANK2 SH3 and multiple ankyrin repeat domains protein 3.051 0.004 A protein-coding gene relating to autism TCF21 Transcription Factor 21 3.030 0.008 augmenting steroidogenic factor (SF) 1 and estrogen receptor β (ERβ) PRDM1 positive regulatory domain 1 2.983 0.012 increased IL-10 + Th17 cells are significantly MIR365A MicroRNA 365a 2.974 0.016 involving posttranscriptional modulation of genes via regulating mRNA stabilization and translation FOXP1 Forkhead Box P1 2.849 0.02 activating Wnt/β-cateninsignaling pathway in endometriosis LOC339803 LOC339803 2.841 0.028 Enhancing HCC invasion and migration via miR-30a-5p/ SNAIL1. In human atherosclerotic lesions, serve as potential biomarkers for lesion hypoxia. ZNF311 Zinc Finger Protein311 2.833 0 upregulated in grade-depended glioma patients of adverse outcome RNASE1 Ribonuclease A Family Member 1 2.773 0.008 a key player in regulation of vascular homeostasis LYPLAL1 Long non coding RNA lysophospholipase -like l 2.771 0.008 Long non coding RNA lysophospholipase-like2 PAX2 Paired Box Homeotic Gene 2 2.670 0.036 Its mutations contribute to optical nerve glioma and kidney dysplasia NUP210L Nucleoporin 210 2.663 0.036 Encoding a membrane-spanning glycoprotein which participates in formation of nuclear pore complex SLC1A2 Solute Carrier Family 1 Member 2 2.657 0.04 Encoding a solute transporter protein MX2 MX Dynamin Like GTPase 2 2.646 0.04 Encoding a protein of dynamin and GTPases families, with nuclear and cytoplasmic forms. SVIL Supervillin 2.632 0.04 Encoded product contributes to myosin II assembly and disintegration of focal adhesions. TERC Telomerase RNA Component 2.614 0.024 Encoding telomerase. PROCA1 Protein Interacting With Cyclin A1 2.588 0.032 Enables cyclin binding activity. Predicted to be involved in arachidonic acid secretion and phospholipid metabolic process ARHGAP25 Rho GTPase Activating Protein 25 2.577 0.004 Encoding negative regulators of Rho GTPases. DAW1 Dynein Assembly Factor With WD Repeats 1 2.569 0.02 Maybe the upstream of some processes, including cerebrospinal fluid circulation; determination of left/right symmetry; and outer dynein arm assembly. MAGI2-AS3 MAGI2 Antisense RNA 3 2.563 0.048 An RNA Gene, affiliated with the lncRNA class. Diseases associated with MAGI2-AS3 include Nephrotic Syndrome, Type 15 and Breast Cancer. TNFSF13B TNF Superfamily Member 13b 2.488 0.036 modulating B cells proliferation and differentiation. HOXA2 Homeobox A2 2.3473 0.008 Encoding a DNA-binding transcription factor governing morphogenesis, and differentiation. SGIP1 SH3GL Interacting Endocytic Adaptor 1 2.103 0.016 May involve in clathrin-mediated endocytosis and energy homeostasis. ASCL2 Achaete-Scute Family BHLH Transcription Factor 2 2.028 0 related pathways are Embryonic and Induced Pluripotent Stem Cells and Lineage-specific Markers and Human Early Embryo Development. EPM2AIP1 EPM2A Interacting Protein 1 2.013 0.028 MLH1 and EPM2AIP1 genes share a common promoter whose methylation has been shown to affect both genes. UBD Ubiquitin D 1.818 0.004 Encoded protein participates in aggresomes formation, mitotic regulation, and dendritic cell maturation. RNF39 RING finger protein 39 1.6484 0.012 Its variants were linked to viral diseases and autoimmune diseases. TBX3 T-Box Transcription Factor 3 1.567 0.004 Regulating developmental processes. PON1 Paraoxonase 1 1.390 0.016 Displaying lactonase and ester hydrolase activity. ZIC1 Zic Family Member 1 1.157 0.032 Encoding a C2H2-type zinc finger proteins. Table 2 Hypermethylation in endometrial tissues compared the endometriosis. Gene Symbol Gene name Fold Change Ratio(Endometrial vs Cyst) P value Function TNXB Tenascin XB -1.083 0.044 The tenascins possess anti-adhesive effects. CD81 CD81 Molecule -1.975 0.032 Modulating cell activation, growth and motility. SHF Src Homology 2 Domain Containing F -2.107 0.016 May enable phosphotyrosine residue binding activation, and participate in apoptosis. ESR1 Estrogen Receptor 1 -2.177 0.016 Encoding estrogen receptor, vital for hormone binding, and transcriptional activation. ESR2 Estrogen Receptor 2 -2.280 0.036 Encoding the estrogen receptor 2. RBM24 RNA Binding Motif Protein 24 -2.414 0.036 Involved in several processes, including negative regulation of cytoplasmic translation, and regulation of mRNA metabolic process. LMO7DN LIM Domain 7 downstream neighbour -2.487 0.02 Involved in lung cancer prognosis. ZC3H12D Zinc Finger CCCH-Type Containing 12D -2.541 0.02 Predicted to enable endoribonuclease activity and mRNA binding activity, and negatively modulate G1/S transition and cell growth CACNB2 Calcium Voltage-Gated Channel Auxiliary Subunit Beta 2 -2.550 0.02 Encoding a subunit of voltage-dependent calcium channel proteins. C17orf107(CHRNE) Cholinergic Receptor Nicotinic Epsilon Subunit -2.563 0.048 After binding acetylcholine, AChR undergoes an alteration in conformation opening an ionotransduction channels across the plasma membrane HAND2-AS1 HAND2 Antisense RNA 1 -2.605 0.044 Predicted to be involved in positive regulation of gene expression, and possess a positive effect on cardiac right ventricle morphogenesis. PEMT Phosphatidylethanolamine N- Methyltransferase -2.800 0.028 Converting phosphatidylethanolamine to phosphatidylcholine by sequential methylation. ZNF22 Zinc Finger Protein22 -2.837 0.012 Modulating cell migration, adhesion, and cycle. STRA6 Signaling Receptor And Transporter Of Retinol STRA6 -3.033 0 Encoding a membrane protein responsible for retinol metabolism. LINC00460 Long Intergenic Non-Protein Coding RNA 460 -3.090 0.004 play vital roles in the pathogenesis, tumorigenesis, and angiogenesis of cancers. LRMDA Leucine Rich Melanocyte Differentiation Associated -3.270 0.004 This gene encodes a leucine-rich repeat protein. EMX2OS EMX2OS -3.272 0 Modulating ovarian cancer cells through miR-654-3p/AKT3/PD-L1. RNF19A RING finger protein 19A -3.461 0 Interacting with alpha synuclein in neurons. HOXC4 Homeobox C4 -3.463 0 Related to immunodeficiency with Hyper-Igm, and lymphoma. TFAMP1 Transcription Factor A, Mitochondrial Pseudogene 1 -3.641 0.004 Encoding a mitochondrial transcription factor. FMN1 Formin 1 -4.035 0 Modulating development of adhesion junction and linear actin polymerization. We compared our differentially methylated sites and only found consistent results on hyper-methylation on ESR1 [ 1 , 12 ].Consistently, downregulation of ESR1 mRNA level in endometriosis was also reported in few studies [ 12 , 13 ]. Then we searched for the literature for the differentially methylated genes we identified and examined whether the associated expression patterns were observed. Indeed, we observed consistent results on 5 genes: TNFSF13B , FOXP1 , TCF21 , BST2 and STRA6 [ 14 – 20 ].Taken together, despite little overlap with previously characterized genes, the characterized methylated genes in endometriosis were consistent with the reported expression changes in endometriosis(Table 3 ). Table 3 The differentially methylated genes were consistent with the reported expression changes in endometriosis. Gene Symbol Gene name Fold Change Ratio(Endometrial vs Cyst) P value Function Hypomethylation BST2 bone marrow stromal cell antigen 2 3.612 0 Regulating type-I interferon and interleukin-6 generation Modulating embryo-maternal immune. TCF21 Transcription Factor 21 3.030 0.008 Interacting with upstream stimulatory factor 2, transactivating SF-1 and Erβ promoters, and modulating estrogen pathway and fibrosis in endometriosis. FOXP1 Forkhead Box P1 2.849 0.02 FOXP1 activating Wnt/β-cateninsignaling pathway in endometriosis.Its knockdown reverted endometrium cell phenotypes. TNFSF13B TNF Superfamily Member 13b 2.488 0.036 Modulating B cells proliferation and differentiation. Increased in serum of endometriosis subjects. Hypermethylation ESR1 Estrogen Receptor 1 -2.177 0.016 Encoding estrogen receptor, vital for hormone binding, and transcriptional activation. STRA6 Signaling Receptor And Transporter Of Retinol STRA6 -3.033 0 Vital for retinol binding protein, the retinol uptake into cells. Downregulating STRA6 enhanced endogenous estradiol synthesis. PEMT Phosphatidylethanolamine N- Methyltransferase -2.800 0.028 Converting phosphatidylethanolamine to phosphatidylcholine by sequential methylation. Its polymorphism may induce infertility of endometriosis women. Discussion In this work, we presented a very small cohort of paired DNA methylation analysis of normal ovarian, endometrial and endometriosis samples. Despite the very small sample size, results were very clear that endometriosis samples closely resembled normal ovarian tissues, but not endometrial tissues. Such results suggested that, instead of migrating from endometrial tissues, endometriosis might be originated from ovarian tissues. Such results did not rule out the possibility that endometriosis was indeed seeded by endometrial cells, but drastic DNA methylation reprogramming resulted in highly similar DNA methylation profiles to the ovarian tissues. A recent province confirmed genome-wide DNA methylation profiles of endometriosis tissue subtypes, focusing on promoters [ 21 ]. They found a large number of methylation differences compared with the eutopic endometrium and verified with clinical data. At the same time, Yoshiaki et al revealed a more accurate genome-wide DNA methylation map, which was derived from the homogenous ESCs of eutopic endometrium and ovarian endometrium cysts with endometriosis. Some differentially methylated or expressed genes (Nr5a1, star, STRA6 and HSD17B2) were involved in steroidogenesis, also verified in numerous clinical specimens by independent methods [ 20 ]. Our strategy was to investigate whether there were methylation differences between multilocular ovarian cysts and unilocular ovarian cysts and normal ovarian tissues. Many genes in choESC acquired from endometrium cysts had different degrees of methylation. Basing on acquired methylation profiles, specific features of aberrantly methylated genes in choESC were evaluated using gene cards (the humor gene database) analysis. There are abnormalities of relevant signal transduction pathways in endometriosis pathogenesis and progression. Abnormal methylation status exists in genes related to proliferation and apoptosis, and immune responses, indicating an abnormal expression of choESC in peritoneal environment. Meanwhile, choesc showed abnormal differentiation, such as neurogenesis and embryogenesis. This means that choesc may have differentiated into other types of cells, suggesting the existence of abnormal developmental processes. The above findings add the possible involvement of DNA epigenetic modifications in endometriosis pathogenesis. We compared our differentially methylated sites and only found consistent results on hyper-methylation on ESR1. Consistently, downregulation of ESR1 mRNA level in endometriosis was also reported in few studies. Then we searched for the literature for the differentially methylated genes we identified and examined whether the associated expression patterns were observed. Indeed, we observed consistent results on 5 genes: TNFSF13B, FOXP1, TCF21, BST2 PEMT and STRA6. Increased TNFSF13B B lymphocyte stimulator protein was identified in serum of endometriosis subjects [ 14 ]. Suppressing FOXP1 reverted the endometrium cell phenotype, involving decreased collagen gel contraction, cell growth and migratory movement [ 15 ].TCF21 could transactivate SF-1 and Erβ promoters in ESCs [ 16 ], modulating estrogen pathway and fibrosis of endometriosis[ 17 ]. rs4244593 of PEMT-related polymorphism modulated the choline or phospholipids generation, inducing infertility of endometriosis women [ 19 ].STRA6 is vital for retinol binding protein, and retinol uptake into cells. The correlation analysis between DNA methylation and transcriptomes identified an anticipated positive relation, as well as a negative relation. It is impossible to characterize the close relationship between DNA methylation and mRNA expression due to the lesser gene coverage of beadchip specifications and the analysis of only two CPGs per gene. In genome-wide observation, a complex network may exist between DNA methylation and transcription. Altogether, this study provides basic DNA methylation data on ovarian endometriosis compared with ovarian tissue and eutopic endometrium using untreated cultured ESCs. We believe that this kind of new information will contribute to the future research on treatment strategies and preventive drugs for endometriosis. Declarations Acknowledgements This work is funded by National Natural Science Foundation of China (31871332) and ShanghaiTech University. We thank ShanghaiTech University and Y. Zhang for the HPC platform and technical support. Funding Research reported in this publication was supported by funding from research start-up funds from Tongji University School of Medicine（2018A05）. The content is solely the responsibility of the authors and does not necessarily represent the official views . Author contributions Xiaohui Zhang and Jinhong Chen conceived the study. Xiaojing Zhao and Jiapo Wang performed the data analysis. Xiaohui Zhang, Jiapo Wang and Yifang,Zhang performed the sample collection. Xiaohui Zhang, Xiaojing Zhao and Jiapo Wang wrote the manuscript. Ethics declarations The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine (approval No. [KS1937]), and informed consent was taken from all the patients. Competing interests No competing interests. Supplementary description Differential DNA methylation between endometriosis and endometrial tissues and identified the differentially methylated regions. Availability of data and materials The data used to support this manuscript and all supplementary materials are reported in its entirety. 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Ganieva U, Nakamura T, Osuka S, Bayasula, Nakanishi N, Kasahara Y, Takasaki N, Muraoka A, Hayashi S, Nagai T, et al: Involvement of Transcription Factor 21 in the Pathogenesis of Fibrosis in Endometriosis. Am J Pathol 2020, 190:145–157. Vestergaard AL, Knudsen UB, Munk T, Rosbach H, Martensen PM: Transcriptional expression of type-I interferon response genes and stability of housekeeping genes in the human endometrium and endometriosis. Mol Hum Reprod 2011, 17:243–254. Szczepańska M, Mostowska A, Wirstlein P, Lianeri M, Marianowski P, Skrzypczak J, Jagodziński PP: Polymorphic variants of folate and choline metabolism genes and the risk of endometriosis-associated infertility. Eur J Obstet Gynecol Reprod Biol 2011, 157:67–72. Yamagata Y, Nishino K, Takaki E, Sato S, Maekawa R, Nakai A, Sugino N: Genome-wide DNA methylation profiling in cultured eutopic and ectopic endometrial stromal cells. PLoS One 2014, 9:e83612. Borghese B, Barbaux S, Mondon F, Santulli P, Pierre G, Vinci G, Chapron C, Vaiman D: Research resource: genome-wide profiling of methylated promoters in endometriosis reveals a subtelomeric location of hypermethylation. Mol Endocrinol 2010, 24:1872–1885. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3446301","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":241100123,"identity":"b74299df-59dd-4b71-950e-44de757ca8e5","order_by":0,"name":"Xiaohui Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYBACNvbmww8+VEjwABkHHyRU1BDWwsdzLM1wxhkLGSAj2eDBmWOEtchJ5BhI87ZV2MhJ+JhJPmxhJsJhPGcMjHnOAB0mwWNWkdjAxsDf3p1AwC9tBQ/ngPwi3VZ2I3GHDIPEmbMbCNhyeIPBG5AtMoe33Ug8w8ZgIJFLQItEgoEEbxvIYQlmBYltzMRoSTGQhGhJMWMgTgskkIFagIEskXDmGA9Bv8i3g6Oyzh7IOPjxR0WNHH97L34tGICHNOWjYBSMglEwCrACAKQSR11Dh9W7AAAAAElFTkSuQmCC","orcid":"","institution":"Tong Ji University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Xiaohui","middleName":"","lastName":"Zhang","suffix":""},{"id":241100126,"identity":"c1fc7514-96c6-41cb-a4cd-a765a3f2af01","order_by":1,"name":"Xiaojing Zhao","email":"","orcid":"","institution":"ShanghaiTech University","correspondingAuthor":false,"prefix":"","firstName":"Xiaojing","middleName":"","lastName":"Zhao","suffix":""},{"id":241100129,"identity":"0354e67f-43ee-4e50-8a5b-1ddb052e4000","order_by":2,"name":"Jiapo Wang","email":"","orcid":"","institution":"Tong Ji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jiapo","middleName":"","lastName":"Wang","suffix":""},{"id":241100132,"identity":"025f5291-213f-405a-8e44-4d553da75a0f","order_by":3,"name":"Zhang Yifang","email":"","orcid":"","institution":"Changxing People’s Hospital of Zhejiang Province","correspondingAuthor":false,"prefix":"","firstName":"Zhang","middleName":"","lastName":"Yifang","suffix":""},{"id":241100134,"identity":"717c28e2-492e-4408-999f-2b964c1fe980","order_by":4,"name":"Jinhong Chen","email":"","orcid":"","institution":"Tong Ji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jinhong","middleName":"","lastName":"Chen","suffix":""},{"id":241100136,"identity":"14558620-8c3f-4033-b3cf-12ead87e5e56","order_by":5,"name":"Jinzhong Chen","email":"","orcid":"","institution":"Tong Ji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jinzhong","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2023-10-14 16:14:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3446301/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3446301/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":45102327,"identity":"7f545751-fe65-4ced-b182-90ae630066f0","added_by":"auto","created_at":"2023-10-23 17:51:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":208702,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA.\u003c/strong\u003ePCA plot of DNA methylation data from endometriosis, normal ovarian and endometrial tissues. \u003cstrong\u003eB.\u003c/strong\u003eOne of endometrial sample was located further away from other samples as an outlier, and this sample also showed a slightly different normalized beta distribution compared with other samples. \u003cstrong\u003eC. \u003c/strong\u003eEndometriosis samples closely resembled normal ovarian tissues, but not endometrial tissues.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3446301/v1/3f95454bc785a2b304db5e1a.png"},{"id":45102783,"identity":"4b57b302-bdc5-4203-90bf-b7c899f36449","added_by":"auto","created_at":"2023-10-23 18:07:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":532901,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3446301/v1/6a11e6cc-5e68-4202-92bc-9750edaef540.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"DNA methylation profiles of ovarian cysts resemble ovarian tissues, but not endometrial tissues","fulltext":[{"header":"Background","content":"\u003cp\u003eOvarian endometriosis has a high prevalence and affects millions of women worldwide. The origin of endometriosis is still puzzling. It is generally considered to be derived from endometrium[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], however, other hypotheses were also provided. For instance, a latest report suggested that ~\u0026thinsp;60% of endometriosis may originate from fallopian tube[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].Ovarian origin recently, researchers found and confirmed the existence of cells expressing two germ cell line specific proteins (deadboxpolypeptide4/interferoninducedtrans, membraneprotein3, ddx4/ifitm3) in ectopic ovarian EMS lesions, suggesting that ovary-originated stem cell may contribute to the occurrence and progression of ovary EMS lesions [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. To answer this question, we resorted to paired DNA methylation assay for ovarian endometriosis, normal ovarian and endometrial tissues in a small pilot cohort.\u003c/p\u003e \u003cp\u003eEpigenetic modifications regulate the transcriptional process, and abnormalities lead to various diseases. Among the most investigated and vital modifications, DNA methylation was linked to alterations in endometrial function/dysfunction-related genes, modulating cell proliferation, inflammation/immune response, angiogenesis, and steroid hormone response. These findings offer a deep understanding of epigenetic reprogramming and steroid hormone effects in endometrium aiding in the pathogenesis and pathophysiology of endometriosis [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious reports have shown that the endometriosis pathophysiology involves aberrant promoter methylation of several genes, for instance, HOXA10 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], steroidogenic factor 1 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and aromatase [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. As a new research area, genome-wide DNA methylation analysis can clarify the relationship between DNA methylation state and endometriosis. Our study utilized a microarray-based approach to determine the accurate DNA methylation level. The abnormal methylation expression between ovarian endometriosis cells, eutopic endometrium and ovarian tissues was analyzed.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cb\u003eSample Collection.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eEndometrium was biopsied from 4 fertile women receiving surgery for histologically confirmed unilocular/multilocular ovarian endometriosis (2:2). Normal ovarian tissue and eutopic endometrium of the same patient were used as controls. Specimens were obtained from subjects without hormone-based treatments at least 1 quarter before specimen acquisition and menstruation just clean, that is, endometrial hyperplasia. Upon surgical dissection, partial tissue was cryopreserved for microarray analyses. Endometrium and cysts were rinsed by Dulbecco's modified eagle's medium (DMEM) comprising of glutamine, 50mg/ml streptomycin, and 50iu/ml penicillin (all from Invitrogen, Paisley, UK), and subsequently cut to a size of 1mm\u003csup\u003e3\u003c/sup\u003e. Then, ESC was isolated via screening with 70mm nylon mesh after 2 hours of collagenase (Sigma, Mo, USA) procession in a shaking incubator at 37℃. The filtrate was washed three times. The human investigation committee of Tongji University endorsed the research.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDNA methylation analysis\u003c/h2\u003e \u003cp\u003eIllumina 850k methylation EPIC Bead Array data was processed through a standard pipeline using the ChAMP package in R. The ChAMP can load raw intensity data in the form of IDAT or matrix containing methylation value (beta) of each probe[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. After filtering and normalization, the 12 samples were combined into an array including only overlapping CpG sites and finally 743,800 probes were included. Principal component analysis (PCA) was firstly run on normalized methylation data to evaluate the similarity of methylation profile in 12 samples.\u003c/p\u003e \u003cp\u003eBumphunter method was implemented to identify differentially methylated regions (DMR) within ChAMP (ChAMP.DMR function). The methylation beta value of each DMR was calculated using the mean value of all the probes that included in each DMR. The heatmap was drawn using all the DMRs within 12 samples. The Family-wise error rate (FWER) adjusted p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered a statistical significance threshold. Therefore, the DMR regions with a FWER\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered as significantly differentially methylated regions. The genomic regions for significantly differentially methylated regions were annotated with the definition of TSS3000 (3000 upstream and downstream of transcription initiation locus respectively) as the promoter region.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003eDNA methylation profiles showed the ovarian cysts were closely grouped with normal ovarian but not endometrial tissues.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTotal of 12 samples from 4 patients, each with endometriosis, ovarian and endometrial tissues were profiled with illumina 850k methylation array. Principal component analysis clearly showed that endometriosis samples were tightly clustered with samples of ovarian tissue (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). One of endometrial sample was located further away from other samples as an outlier, and this sample also showed a slightly different normalized beta distribution compared with other samples (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Therefore, we removed this sample for the downstream analyses. To confirm this result, we also performed PCA on our samples as well as publically available DNA methylation data on healthy endometrial biopsies[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and as expected, healthy endometrial samples from public data were closer to our endometrial samples (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAbnormal epigenetic profiles of genes involving receptors, signaling pathways and immune responses\u003c/h2\u003e \u003cp\u003eMost of previous studies compared the endometriosis with endometrial tissues; therefore we analyzed differential DNA methylation between endometriosis and endometrial tissues and identified the differentially methylated regions (TableS1). In comparison with eutopic endometriosis, many genes in ovarian endometrial cysts (choESC) had different degrees of methylation, high and low (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e),With acquired methylation profiles data, we identified the detailed features of aberrantly methylated genes in choESC using gene cards (the humor gene database) analyses. Depending on pathway analysis of screened genes, there are abnormalities of relevant signal transduction pathways involving endometriosis onset and progression, developmental processes, human early embryonic development, regulation of caspase, tyrosine, and mRNA metabolic processes et al. It indicated an abnormal expression pattern of choESC in peritoneal environment. As analyzed by GO and KEGG, the genes were primarily engaged in epithelial-mesenchymal transition(EMT), adhesion integrity, apoptosis, proliferation, and cell differentiation, et.al.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHypomethylation in endometrial tissues compared the endometriosis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene Symbol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGene name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFold Change Ratio(Endometrial vs Cyst)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFunction\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOXB1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ehomeotic genes B1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.749\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eImportant growth and development regulatory genes regulator of retinoic acid\u003c/p\u003e \u003cp\u003eresponse elements (RAREs)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emembrane compartment of Can1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.709\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eone cytoplasm membrane microdomain regulating metabolism, cellular morphogenesis, signaling cascades, and mRNA degradation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTMEM101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etransmembrane protein 101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.695\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eupregulation and increase the expression of NF-κB in ovary cancer.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCASS4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHomo sapiens Cas scaffolding protein family\u003c/p\u003e \u003cp\u003e member 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.624\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePossible docking protein which may play a role for tyrosine-kinase-based signaling\u003c/p\u003e \u003cp\u003erelated to cell adhesion. Regulates FAK\u003c/p\u003e \u003cp\u003eactivity, focal adhesion integrity, and cell \u003c/p\u003e \u003cp\u003espreading.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBST2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebone marrow stromal cell antigen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.612\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRegulating Type-I interferon and interleukin-6 generation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFABP3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFatty Acid Binding Protein 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDuring the early stages of pregnancy, upregulating cell growth and proliferation in uterine endometrium\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFAIM2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFas Apoptotic Inhibitory Molecule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003especifically protecting cells from Fas-induced apoptosis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSHANK2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSH3 and multiple ankyrin\u003c/p\u003e \u003cp\u003e repeat domains protein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.051\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA protein-coding gene relating to autism\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTCF21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTranscription Factor 21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eaugmenting steroidogenic factor (SF) 1 and \u003c/p\u003e \u003cp\u003eestrogen receptor β (ERβ)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePRDM1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epositive regulatory domain 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.983\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eincreased IL-10\u0026thinsp;+\u0026thinsp;Th17 cells are significantly\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMIR365A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMicroRNA 365a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.974\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003einvolving posttranscriptional modulation of genes via regulating mRNA stabilization and translation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFOXP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eForkhead Box P1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.849\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eactivating Wnt/β-cateninsignaling pathway \u003c/p\u003e \u003cp\u003ein endometriosis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLOC339803\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLOC339803\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.841\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEnhancing HCC invasion and migration via miR-30a-5p/ SNAIL1. \u003c/p\u003e \u003cp\u003eIn human atherosclerotic lesions, serve as potential biomarkers for lesion hypoxia.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZNF311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZinc Finger Protein311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eupregulated in grade-depended glioma patients of adverse outcome\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRNASE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRibonuclease A Family Member 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.773\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ea key player in regulation of vascular homeostasis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLYPLAL1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLong non coding RNA lysophospholipase\u003c/p\u003e \u003cp\u003e-like l\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.771\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLong non coding RNA lysophospholipase-like2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePAX2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePaired Box Homeotic Gene 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.670\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIts mutations contribute to optical nerve glioma and kidney dysplasia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNUP210L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNucleoporin 210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.663\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding a membrane-spanning glycoprotein which participates in formation of nuclear pore complex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSLC1A2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolute Carrier Family 1 Member 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.657\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding a solute transporter protein\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMX2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMX Dynamin Like GTPase 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.646\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding a protein of dynamin and GTPases families, with nuclear and cytoplasmic forms.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSVIL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSupervillin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.632\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoded product contributes to myosin II assembly and disintegration of focal adhesions.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTERC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTelomerase RNA Component\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.614\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding telomerase.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePROCA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProtein Interacting With Cyclin A1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.588\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEnables cyclin binding activity. Predicted to be\u003c/p\u003e \u003cp\u003e involved in arachidonic acid secretion and \u003c/p\u003e \u003cp\u003ephospholipid metabolic process\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eARHGAP25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRho GTPase Activating Protein 25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.577\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding negative regulators of Rho GTPases.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDAW1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDynein Assembly Factor With WD\u003c/p\u003e \u003cp\u003eRepeats 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.569\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMaybe the upstream of some processes, including cerebrospinal fluid circulation; determination of left/right symmetry; and outer dynein arm assembly.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAGI2-AS3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMAGI2 Antisense RNA 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.563\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAn RNA Gene, affiliated with the\u003c/p\u003e \u003cp\u003elncRNA class. Diseases associated with MAGI2-AS3 include Nephrotic Syndrome,\u003c/p\u003e \u003cp\u003eType 15 and Breast Cancer.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNFSF13B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTNF Superfamily Member 13b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.488\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emodulating B cells proliferation and \u003c/p\u003e \u003cp\u003edifferentiation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOXA2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHomeobox A2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.3473\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding a DNA-binding\u003c/p\u003e \u003cp\u003etranscription factor governing morphogenesis, \u003c/p\u003e \u003cp\u003eand differentiation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGIP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSH3GL Interacting Endocytic Adaptor 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMay involve in clathrin-mediated endocytosis and energy homeostasis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASCL2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAchaete-Scute Family BHLH\u003c/p\u003e \u003cp\u003eTranscription\u003c/p\u003e \u003cp\u003eFactor 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003erelated pathways are Embryonic and Induced\u003c/p\u003e \u003cp\u003e Pluripotent Stem Cells and Lineage-specific\u003c/p\u003e \u003cp\u003e Markers and Human Early Embryo Development.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEPM2AIP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEPM2A Interacting Protein 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMLH1 and EPM2AIP1 genes share a common\u003c/p\u003e \u003cp\u003e promoter whose methylation has been shown to affect both genes.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUbiquitin D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.818\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoded protein participates in aggresomes formation, mitotic regulation, and dendritic cell maturation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRNF39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRING finger protein 39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.6484\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIts variants were linked to viral diseases and autoimmune diseases.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTBX3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT-Box Transcription Factor 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.567\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRegulating developmental processes.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePON1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParaoxonase 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.390\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDisplaying lactonase and ester hydrolase activity.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZIC1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZic Family Member 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding a C2H2-type zinc finger proteins.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHypermethylation in endometrial tissues compared the endometriosis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene Symbol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGene name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFold Change Ratio(Endometrial vs Cyst)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFunction\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNXB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTenascin XB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-1.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThe tenascins possess anti-adhesive effects.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCD81 Molecule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-1.975\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eModulating cell activation, growth and motility.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSHF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSrc Homology 2 Domain Containing F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMay enable phosphotyrosine residue \u003c/p\u003e \u003cp\u003ebinding activation, and participate in apoptosis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEstrogen Receptor 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding estrogen receptor, vital for hormone binding, and transcriptional activation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEstrogen Receptor 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding the estrogen receptor 2.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRBM24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRNA Binding Motif Protein 24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.414\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eInvolved in several processes, including negative regulation of cytoplasmic translation, and regulation of mRNA metabolic process.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLMO7DN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLIM Domain 7 downstream neighbour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.487\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eInvolved in lung cancer prognosis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZC3H12D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZinc Finger CCCH-Type Containing\u003c/p\u003e \u003cp\u003e12D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.541\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePredicted to enable endoribonuclease activity and mRNA binding activity, and negatively modulate G1/S transition and cell growth\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCACNB2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCalcium Voltage-Gated Channel\u003c/p\u003e \u003cp\u003eAuxiliary Subunit Beta 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.550\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding a subunit of voltage-dependent calcium channel proteins.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC17orf107(CHRNE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCholinergic Receptor Nicotinic Epsilon\u003c/p\u003e \u003cp\u003eSubunit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.563\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAfter binding acetylcholine, AChR undergoes an alteration in conformation opening an ionotransduction channels across the plasma membrane\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHAND2-AS1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHAND2 Antisense RNA 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.605\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePredicted to be involved in positive regulation of gene expression, and possess a positive effect on cardiac right ventricle morphogenesis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePEMT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhosphatidylethanolamine N-\u003c/p\u003e \u003cp\u003eMethyltransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.800\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eConverting phosphatidylethanolamine to phosphatidylcholine by sequential\u003c/p\u003e \u003cp\u003emethylation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZNF22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZinc Finger Protein22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.837\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eModulating cell migration, adhesion, and cycle.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSTRA6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSignaling Receptor And Transporter Of\u003c/p\u003e \u003cp\u003eRetinol\u003c/p\u003e \u003cp\u003eSTRA6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-3.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding a membrane protein responsible for retinol metabolism.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLINC00460\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLong Intergenic Non-Protein Coding\u003c/p\u003e \u003cp\u003eRNA 460\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-3.090\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eplay vital roles in the pathogenesis, tumorigenesis, \u003c/p\u003e \u003cp\u003eand angiogenesis of cancers.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLRMDA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeucine Rich Melanocyte Differentiation\u003c/p\u003e \u003cp\u003eAssociated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-3.270\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThis gene encodes a leucine-rich repeat protein.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEMX2OS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEMX2OS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-3.272\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eModulating ovarian cancer cells through miR-654-3p/AKT3/PD-L1.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRNF19A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRING finger protein 19A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-3.461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eInteracting with alpha synuclein in neurons.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOXC4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHomeobox C4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-3.463\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRelated to immunodeficiency with Hyper-Igm, and lymphoma.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTFAMP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTranscription Factor A, Mitochondrial\u003c/p\u003e \u003cp\u003ePseudogene 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-3.641\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding a mitochondrial transcription factor.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFMN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFormin 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-4.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eModulating development of adhesion junction\u003c/p\u003e \u003cp\u003eand linear actin polymerization.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe compared our differentially methylated sites and only found consistent results on hyper-methylation on \u003cem\u003eESR1\u003c/em\u003e [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].Consistently, downregulation of \u003cem\u003eESR1\u003c/em\u003e mRNA level in endometriosis was also reported in few studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Then we searched for the literature for the differentially methylated genes we identified and examined whether the associated expression patterns were observed. Indeed, we observed consistent results on 5 genes: \u003cem\u003eTNFSF13B\u003c/em\u003e, \u003cem\u003eFOXP1\u003c/em\u003e, \u003cem\u003eTCF21\u003c/em\u003e, \u003cem\u003eBST2\u003c/em\u003e and \u003cem\u003eSTRA6\u003c/em\u003e [\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].Taken together, despite little overlap with previously characterized genes, the characterized methylated genes in endometriosis were consistent with the reported expression changes in endometriosis(Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe differentially methylated genes were consistent with the reported expression changes in endometriosis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene Symbol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGene name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFold Change Ratio(Endometrial vs Cyst)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFunction\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypomethylation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBST2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebone marrow stromal cell antigen 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.612\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRegulating type-I interferon and interleukin-6 generation\u003c/p\u003e \u003cp\u003eModulating embryo-maternal immune.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTCF21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTranscription Factor 21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eInteracting with upstream stimulatory factor 2, transactivating SF-1 and Erβ promoters, and modulating estrogen pathway and fibrosis in endometriosis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFOXP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eForkhead Box P1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.849\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFOXP1 activating Wnt/β-cateninsignaling pathway in endometriosis.Its knockdown reverted endometrium cell phenotypes.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNFSF13B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTNF Superfamily Member 13b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.488\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eModulating B cells proliferation and \u003c/p\u003e \u003cp\u003edifferentiation. Increased in serum of endometriosis subjects.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypermethylation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEstrogen Receptor 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEncoding estrogen receptor, vital for hormone binding, and transcriptional activation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSTRA6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSignaling Receptor And Transporter Of\u003c/p\u003e \u003cp\u003eRetinol\u003c/p\u003e \u003cp\u003eSTRA6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-3.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVital for retinol binding protein, the retinol uptake into cells. Downregulating STRA6 enhanced endogenous estradiol synthesis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePEMT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhosphatidylethanolamine N-\u003c/p\u003e \u003cp\u003eMethyltransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.800\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eConverting phosphatidylethanolamine to phosphatidylcholine by sequential methylation. Its polymorphism may induce infertility of endometriosis women.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this work, we presented a very small cohort of paired DNA methylation analysis of normal ovarian, endometrial and endometriosis samples. Despite the very small sample size, results were very clear that endometriosis samples closely resembled normal ovarian tissues, but not endometrial tissues. Such results suggested that, instead of migrating from endometrial tissues, endometriosis might be originated from ovarian tissues. Such results did not rule out the possibility that endometriosis was indeed seeded by endometrial cells, but drastic DNA methylation reprogramming resulted in highly similar DNA methylation profiles to the ovarian tissues.\u003c/p\u003e \u003cp\u003eA recent province confirmed genome-wide DNA methylation profiles of endometriosis tissue subtypes, focusing on promoters [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. They found a large number of methylation differences compared with the eutopic endometrium and verified with clinical data. At the same time, Yoshiaki et al revealed a more accurate genome-wide DNA methylation map, which was derived from the homogenous ESCs of eutopic endometrium and ovarian endometrium cysts with endometriosis. Some differentially methylated or expressed genes (Nr5a1, star, STRA6 and HSD17B2) were involved in steroidogenesis, also verified in numerous clinical specimens by independent methods [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Our strategy was to investigate whether there were methylation differences between multilocular ovarian cysts and unilocular ovarian cysts and normal ovarian tissues.\u003c/p\u003e \u003cp\u003eMany genes in choESC acquired from endometrium cysts had different degrees of methylation. Basing on acquired methylation profiles, specific features of aberrantly methylated genes in choESC were evaluated using gene cards (the humor gene database) analysis. There are abnormalities of relevant signal transduction pathways in endometriosis pathogenesis and progression. Abnormal methylation status exists in genes related to proliferation and apoptosis, and immune responses, indicating an abnormal expression of choESC in peritoneal environment. Meanwhile, choesc showed abnormal differentiation, such as neurogenesis and embryogenesis. This means that choesc may have differentiated into other types of cells, suggesting the existence of abnormal developmental processes. The above findings add the possible involvement of DNA epigenetic modifications in endometriosis pathogenesis.\u003c/p\u003e \u003cp\u003eWe compared our differentially methylated sites and only found consistent results on hyper-methylation on ESR1. Consistently, downregulation of ESR1 mRNA level in endometriosis was also reported in few studies. Then we searched for the literature for the differentially methylated genes we identified and examined whether the associated expression patterns were observed. Indeed, we observed consistent results on 5 genes: TNFSF13B, FOXP1, TCF21, BST2 PEMT and STRA6. Increased TNFSF13B B lymphocyte stimulator protein was identified in serum of endometriosis subjects [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Suppressing FOXP1 reverted the endometrium cell phenotype, involving decreased collagen gel contraction, cell growth and migratory movement [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].TCF21 could transactivate SF-1 and Erβ promoters in ESCs [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], modulating estrogen pathway and fibrosis of endometriosis[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. rs4244593 of PEMT-related polymorphism modulated the choline or phospholipids generation, inducing infertility of endometriosis women [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].STRA6 is vital for retinol binding protein, and retinol uptake into cells.\u003c/p\u003e \u003cp\u003eThe correlation analysis between DNA methylation and transcriptomes identified an anticipated positive relation, as well as a negative relation. It is impossible to characterize the close relationship between DNA methylation and mRNA expression due to the lesser gene coverage of beadchip specifications and the analysis of only two CPGs per gene. In genome-wide observation, a complex network may exist between DNA methylation and transcription.\u003c/p\u003e \u003cp\u003eAltogether, this study provides basic DNA methylation data on ovarian endometriosis compared with ovarian tissue and eutopic endometrium using untreated cultured ESCs. We believe that this kind of new information will contribute to the future research on treatment strategies and preventive drugs for endometriosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cdiv\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work is funded by National Natural Science Foundation of China (31871332) and ShanghaiTech University. We thank ShanghaiTech University and Y. Zhang for the HPC platform and technical support.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch reported in this publication was supported by funding from research start-up funds from Tongji University School of Medicine（2018A05）. The content is solely the responsibility of the authors and does not necessarily represent the official views .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXiaohui Zhang and Jinhong Chen conceived the study. Xiaojing Zhao and Jiapo Wang performed the data analysis. Xiaohui Zhang, Jiapo Wang and Yifang,Zhang performed the sample collection. Xiaohui Zhang, Xiaojing Zhao and Jiapo Wang wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine (approval No. [KS1937]), and informed consent was taken from all the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary description\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDifferential DNA methylation between endometriosis and endometrial tissues and identified the differentially methylated regions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used to support this manuscript and all supplementary materials are reported in its entirety. Because of privacy and ethical issues, patient-level data cannot be reported. Readers may request to access this data for non-commercial use via email to the corresponding author, with an explanation of the detailed intended purposes for the data.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWang Y, Nicholes K, Shih IM: The Origin and Pathogenesis of Endometriosis. Annu Rev Pathol 2020, 15:71\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuan Z, Wang L, Wang Y, Zhang T, Li L, Cragun JM, Chambers SK, Kong B, Zheng W: Tubal origin of ovarian endometriosis. Mod Pathol 2014, 27:1154\u0026ndash;1162.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFraunhoffer NA, Meilerman Abuelafia A, Stella I, Galliano S, Barrios M, Vitullo AD: Identification of germ cell-specific VASA and IFITM3 proteins in human ovarian endometriosis. J Ovarian Res 2015, 8:66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBulun SE: Endometriosis. N Engl J Med 2009, 360:268\u0026ndash;279.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, Osteen K, Lessey BA, Giudice LC: Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology 2003, 144:2870\u0026ndash;2881.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC: Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 2007, 148:3814\u0026ndash;3826.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo SW: Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. 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Mol Endocrinol 2010, 24:1872\u0026ndash;1885.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ovarian endometriosis, DNA methylation, tissue of origin","lastPublishedDoi":"10.21203/rs.3.rs-3446301/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3446301/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Despite the high prevalence of ovarian cyst, its origin is still under debate. Prevailing retrograde menstruation model predicts that ectopic endometrial cells migrate and develop into ovarian cysts. However, other models were also proposed. Because DNA methylation states exhibit a tissue specific pattern, we profiled the DNA methylation for ovarian cysts and paired eutopic endometrial and ovarian tissues from four patients. Surprisingly, DNA methylation profiles showed the ovarian cysts were closely grouped with normal ovarian but not endometrial tissues. These results suggested alterative origin of ovarian cysts or strong epigenetic reprogramming of infiltrating endometrial cells after seeding the ovarian tissue.","manuscriptTitle":"DNA methylation profiles of ovarian cysts resemble ovarian tissues, but not endometrial tissues","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-23 17:51:04","doi":"10.21203/rs.3.rs-3446301/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8d27dd8f-c33a-44bb-8fbd-26fb3da246de","owner":[],"postedDate":"October 23rd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-11-01T09:29:39+00:00","versionOfRecord":[],"versionCreatedAt":"2023-10-23 17:51:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3446301","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3446301","identity":"rs-3446301","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}