{"paper_id":"d1772aec-0018-4dd5-b830-4da19bf97b97","body_text":"Abstract\nEndometriosis is a heterogeneous, recalcitrant disease that affects 10% of reproductive-age women. Resistance to conventional therapy critically raises the need for novel treatment options that target specific, dysregulated underlying molecular mechanisms. Dopamine receptor 2 (DRD2) has been shown to be associated with vascularity and fibrosis in endometriosis. Transcription factor KLFII has been implicated in the pathogenesis of several human endocrine and reproductive tract diseases including endometriosis. KLFII recruits epigenetic cofactors for regulation of target genes; dysregulation of critical target genes and associated signaling pathways results in diverse disease phenotypes. KLFII regulates the expression of DRD2 in neurons. We investigated the regulation of DRD2 by KLFII in the established eutopic and ectopic endometrial cell lines as well as in an animal model of endometriosis. KLFII binding and activation of the DRD2 promoter was conserved across species. Promoter activation was reflected in correspondingly increased gene expression in an endometrial cell line and in primary endometriotic cells. In vivo, disease relevance was further evaluated in a surgically induced murine endometriotic model using Klf11 —/— and wild-type mice. Consistent with loss of Klf11-mediated activation, lesions in Klf11—/— animals were associated with progressive fibrosis and decreased Drd2 expression. KLFII binds specific epigenetic corepressors to repress several target genes. Activation of DRD2 by KLFII could not be explained simply by loss of corepressor binding and is thus likely due to selective coactivator recruitment; identification of the precise pathway is the focus of ongoing investigation. Characterization of pharmacologically reversible epigenetic regulatory mechanisms has translational relevance in health and disease.\nSimilar content being viewed by others\nReferences\nBulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and infertility. J Assist Reprod Genet. 2010;27(8):441–447.\nSimoens S, Hummelshoj L, D’Hooghe T. Endometriosis: cost estimates and methodological perspective. Hum Reprod Update. 2007;13(4):395–404.\nOlive DL, Pritts EA. The treatment of endometriosis: a review of the evidence. Ann N Y Acad Sci. 2002;955:360–372; discussion 389-393, 396-406.\nGiudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389–2398.\nCorrea LF, Zheng Y, Delaney AA, Khan Z, Shenoy CC, Daftary GS. TGF-beta induces endometriotic progression via a non-canonical, KLF11-mediated mechanism. Endocrinology. 2016;157(9):3332–3343.\nZheng Y, Tabbaa ZM, Khan Z, et al. Epigenetic regulation of uterine biology by transcription factor KLF11 via posttranslational histone deacetylation of cytochrome p450 metabolic enzymes. Endocrinology. 2014;155(11):4507–4520.\nRogers PA, D’Hooghe TM, Fazleabas A, et al. Defining future directions for endometriosis research: workshop report from the 2011 World Congress of Endometriosis in Montpellier, France. Reprod Sci. 2013;20(5):483–499.\nBonnefond A, Lomberk G, Buttar N, et al. Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus. J Biol Chem. 2011;286(32):28414–28424.\nFernandez-Zapico ME, van Velkinburgh JC, Gutierrez-Aguilar R, et al. MODY7 gene, KLF11, is a novel p300-dependent regulator of Pdx-1 (MODY4) transcription in pancreatic islet beta cells. J Biol Chem. 2009;284(52):36482–36490.\nDaftary GS, Zheng Y, Tabbaa ZM, et al. A novel role of the Sp/ KLF transcription factor KLF11 in arresting progression of endo-metriosis. PLoS One. 2013;8(3):e60165.\nNavarro A, Yin P, Monsivais D, et al. Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma. PLoS One. 2012;7(3):e33284.\nYin P, Lin Z, Reierstad S, et al. Transcription factor KLF11 integrates progesterone receptor signaling and proliferation in uterine leiomyoma cells. Cancer Res. 2010;70(4):1722–1730.\nTabbaa ZM, Zheng Y, Daftary GS. KLF11 epigenetically regulates glycodelin-A, a marker of endometrial biology via histone-modifying chromatin mechanisms. Reprod Sci. 2014;21(3):319–328.\nZheng Y, Khan Z, Zanfagnin V, Correa LF, Delaney AA, Daftary GS. Epigenetic modulation of collagen 1A1: therapeutic implications in fibrosis and endometriosis. Biol Reprod. 2016;94(4):87.\nBeaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63(1):182–217.\nSeo S, Lomberk G, Mathison A, et al. Krüppel-like factor 11 differentially couples to histone acetyltransferase and histone methyltransferase chromatin remodeling pathways to transcriptionally regulate dopamine D2 receptor in neuronal cells. J Biol Chem. 2012;287(16):12723–12735.\nBilibio JP, Matte U, de Conto E, Genro VK, Souza CA, Cunha-Filho JS. Dopamine receptor D2 genotype (3438) is associated with moderate/severe endometriosis in infertile women in Brazil. Fertil Steril. 2013;99(5):1340–1345.\nLessey BA, Ilesanmi AO, Castelbaum AJ, et al. Characterization of the functional progesterone receptor in an endometrial adenocarcinoma cell line (Ishikawa): progesterone-induced expression of the alpha1 integrin [published erratum appears in J Steroid Biochem Mol Biol 1997 Jan;60(1–2):161]. J Steroid Biochem Mol Biol. 1996;59(1):31–39.\nZeitvogel A, Baumann R, Starzinski-Powitz A. Identification of an invasive, N-cadherin-expressing epithelial cell type in endo-metriosis using a new cell culture model. Am J Pathol. 2001;159(5):1839–1852.\nLomberk G, Mathison AJ, Grzenda A, et al. Sequence-specific recruitment of heterochromatin protein 1 via interaction with Kruppel-like factor 11, a human transcription factor involved in tumor suppression and metabolic diseases. J Biol Chem. 2012;287(16):13026–13039.\nIshibashi H, Suzuki T, Suzuki S, et al. Sex steroid hormone receptors in human thymoma. J Clin Endocrinol Metab. 2003;88(5):2309–2317.\nUhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220): 1260419.\nUsiello A, Baik JH, Rougé-Pont F, et al. Distinct functions of the two isoforms of dopamine D2 receptors. Nature. 2000;408(6809):199–203.\nMoyer RA, Wang D, Papp AC, et al. Intronic polymorphisms affecting alternative splicing of human dopamine D2 receptor are associated with cocaine abuse. Neuropsychopharmacology. 2011;36(4):753–762.\nZhang JS, Moncrieffe MC, Kaczynski J, Ellenrieder V, Prendergast FG, Urrutia R. A conserved alphahelical motif mediates the interaction of Sp1-like transcriptional repressors with the corepressor mSin3A. Mol Cell Biol. 2001;21(15):5041–5049.\nDelaney AA, Khan Z, Zheng Y, et al. KLF10 mediated epigenetic dysregulation of epithelial CD40/CD154 promotes endometriosis. Biol Reprod. 2016;95(3):62.\nNovella-Maestre E, Carda C, Ruiz-Sauri A, Garcia-Velasco JA, Simon C, Pellicer A. Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium: a novel molecular target for endometriosis therapy. Biol Reprod. 2010;83(5):866–873.\nButtar NS, DeMars CJ, Lomberk G, et al. Distinct role of Kruppel-like factor 11 in the regulation of prostaglandin E2 biosynthesis. J Biol Chem. 2010;285(15):11433–11444.\nBerger SL. The complex language of chromatin regulation during transcription. Nature. 2007;447(7143):407–412.\nStrahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403(6765):41–45.\nNovella-Maestre E, Carda C, Noguera I, et al. Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis. Hum Reprod. 2009;24(5):1025–1035.\nJohnson A, DiPietro LA. Apoptosis and angiogenesis: an evolving mechanism for fibrosis. FASEB J. 2013;27(10):3893–3901.\nDelgado-Rosas F, Gómez R, Ferrero H, et al. The effects of ergot and non-ergot-derived dopamine agonists in an experimental mouse model of endometriosis. Reproduction. 2011;142(5):745–755.\nErcan CM, Kayaalp O, Cengiz M, et al. Comparison of efficacy of bromocriptine and cabergoline to GnRH agonist in a rat endometriosis model. Arch Gynecol Obstet. 2015;291(5):1103–1111.\nGómez R, Abad A, Delgado F, Tamarit S, Simón C, Pellicer A. Effects of hyperprolactinemia treatment with the dopamine agonist quinagolide on endometriotic lesions in patients with endometriosis-associated hyperprolactinemia. Fertil Steril. 2011;95(3):882–888.e881.\nHamid AM, Madkour WA, Moawad A, Elzaher MA, Roberts MP. Does cabergoline help in decreasing endometrioma size compared to LHRH agonist? A prospective randomized study. Arch Gynecol Obstet. 2014;290(4):677–682.\nLima AP, Moura MD, Rosa e Silva AA. Prolactin and cortisol levels in women with endometriosis. Braz J Med Biol Res. 2006;39(8):1121–1127.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nRights and permissions\nAbout this article\nCite this article\nRichards, E.G., Zheng, Y., Shenoy, C.C. et al. KLFII is an Epigenetic Mediator of DRD2/Dopaminergic Signaling in Endometriosis. Reprod. Sci. 24, 1129–1138 (2017). https://doi.org/10.1177/1933719117698582\nPublished:\nIssue date:\nDOI: https://doi.org/10.1177/1933719117698582","source_license":"CC0","license_restricted":false}