Transcriptional regulation of the non-homologous end joining gene Ligase IV by an intronic regulatory element directs thymocyte development

Transcriptional regulation of the non-homologous end joining gene Ligase IV by an intronic regulatory element directs thymocyte development | 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 Article Transcriptional regulation of the non-homologous end joining gene Ligase IV by an intronic regulatory element directs thymocyte development Patrick Collins, Matthew Estrada, Christopher Gebhardt, Mariam Salem, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5718046/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Sep, 2025 Read the published version in Genes & Immunity → Version 1 posted 9 You are reading this latest preprint version Abstract Double-strand breaks represent the most dangerous form of DNA damage, and in resting cells, these breaks are sealed via the non-homologous end joining (NHEJ) factor Ligase IV (LIG4). Excessive NHEJ may be genotoxic, necessitating multiple mechanisms to control NHEJ activity. However, a clear mechanism of transcriptional control for them has not yet been identified. Here, we examine mechanisms governing Lig4 transcription in mammals, finding that most tissues maintain very low levels of LIG4 production. Select tissues upregulate LIG4, employing different strategies for genomic regulation. In developing lymphocytes, the Lig4 locus is devoid of long-range chromatin contacts; instead, its expression and role in immune development depend upon a promoter-proximal intronic regulatory element. Deletion of the Lig4 intronic regulatory element results in thymocyte-specific loss of Lig4 upregulation, defects in lymphocyte development and altered antigen receptor rearrangement. Our findings show the NHEJ gene, Lig4, is transcriptionally controlled to support stage-specific function concurrent with programmed DSBs. Moreover, we provide an example of how DNA cis-regulatory elements very close to a promoter can have substantial transcriptional effects. Biological sciences/Immunology/Immunogenetics Biological sciences/Genetics/Gene regulation Biological sciences/Immunology/Gene regulation in immune cells Biological sciences/Immunology/Lymphocytes Non-homologous end joining gene regulation V(D)J recombination cis-regulatory element Ligase IV double-strand break response Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations There is NO conflict of interest to disclose. The authors declare that they have no competing interests Supplementary Files SupFigures.pdf Supplemental Figures Cite Share Download PDF Status: Published Journal Publication published 05 Sep, 2025 Read the published version in Genes & Immunity → Version 1 posted Editorial decision: revise 04 Mar, 2025 Review # 1 received at journal 26 Feb, 2025 Review # 2 received at journal 23 Feb, 2025 Reviewer # 2 agreed at journal 16 Feb, 2025 Reviewer # 1 agreed at journal 12 Feb, 2025 Reviewers invited by journal 27 Jan, 2025 Submission checks completed at journal 30 Dec, 2024 First submitted to journal 26 Dec, 2024 Editor assigned by journal 26 Dec, 2024 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. 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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-5718046","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":395926117,"identity":"9bac171f-3379-4fe3-be4e-cd6c99332a33","order_by":0,"name":"Patrick Collins","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYLCCBCBkYGBuPACk5GCCjA041TPDtDA2gLQYE6eFAaYFSCbCVOLUYs5+/tiHBzVpDPztjQ0HHu6oS+/nP2O64QeDjeyGA9i1WPYkM89IOJbDIHHmYMOBxDOHc2fOyDG72cOQZoxLi8GBZGagYyoYDCQSgVraDuRuuMFjdpuB4XAiTi3nH6NoqUs3OH8GpOU/bi03wLbkwLQwJxgcyAFpOYBTi+WMx8YMCcfSeCB+aTtsOHNGWtnNHoNk45k4tJjzJz5m/FGTLMff3nzw4c+2Onl+/sPbbvyosJPtw+UwKM2DQxyPllEwCkbBKBgFuAEAHtdlH7qMcjMAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-4550-4272","institution":"The Ohio State University","correspondingAuthor":true,"prefix":"","firstName":"Patrick","middleName":"","lastName":"Collins","suffix":""},{"id":395926118,"identity":"1326e3c2-6a78-47be-a699-3ddfedd8b50a","order_by":1,"name":"Matthew Estrada","email":"","orcid":"","institution":"The Ohio State University","correspondingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"","lastName":"Estrada","suffix":""},{"id":395926119,"identity":"7da456f9-694b-41fd-b8d4-c753ece96a6b","order_by":2,"name":"Christopher Gebhardt","email":"","orcid":"","institution":"The Ohio State University","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Gebhardt","suffix":""},{"id":395926120,"identity":"4913af6c-dc8b-4c65-9ea2-d379575f477e","order_by":3,"name":"Mariam Salem","email":"","orcid":"","institution":"The Ohio State University","correspondingAuthor":false,"prefix":"","firstName":"Mariam","middleName":"","lastName":"Salem","suffix":""},{"id":395926121,"identity":"dc92543c-5cb5-4508-bb5f-57cf885844d4","order_by":4,"name":"Kruthika Sharma","email":"","orcid":"","institution":"The Ohio State University","correspondingAuthor":false,"prefix":"","firstName":"Kruthika","middleName":"","lastName":"Sharma","suffix":""},{"id":395926122,"identity":"c0865794-6bb8-4187-b96a-f0e0d977a97f","order_by":5,"name":"Craig Bassing","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Craig","middleName":"","lastName":"Bassing","suffix":""},{"id":395926123,"identity":"952ee805-0da7-4ea5-a8c0-aabba0b54e53","order_by":6,"name":"Eugene Oltz","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Eugene","middleName":"","lastName":"Oltz","suffix":""}],"badges":[],"createdAt":"2024-12-26 21:45:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5718046/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5718046/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41435-025-00353-3","type":"published","date":"2025-09-05T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":73021937,"identity":"b70d36a7-e632-4a11-a5bf-db6222fe44e0","added_by":"auto","created_at":"2025-01-06 04:01:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":282596,"visible":true,"origin":"","legend":"\u003cp\u003eA. tSNE representation of mouse single cell RNA-seq, taken from a dataset that processed eighteen different organs (https://tabula-muris.ds.czbiohub.org/). The blue pseudocolor plots show normalized counts for Rag1 and Lig4 transcripts. On bottom, the cells are colored by originating organ. B. Each cell type was extracted from data in A, and then plotted for Lig4 CPM expression and gene rank. The top six Lig4-expression ranked cell clusters are labeled. C. Expression of Lig4, taken as a snapshot from the Immgen microarray data browser (https://www.immgen.org/). Cell type is listed to the left, expression values are shown on top and bottom. D. Pediatric cancer expression analysis from the St. Jude’s web portal (https://pecan.stjude.cloud/). **** p \u0026lt; 0.0001, Student’s T test. E. Pediatric B acute lymphoblastic leukemia (B-ALL) survival data from the Xena web browser (https://xenabrowser.net/) TARGET PAN-CAN dataset. P values show 𝜒𝜒2 statistics.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-5718046/v1/0b06c4ef7681b1399d8abccb.png"},{"id":73021936,"identity":"21ff6928-d48b-494f-a37c-34b27d64653e","added_by":"auto","created_at":"2025-01-06 04:01:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":484326,"visible":true,"origin":"","legend":"\u003cp\u003eChromatin landscape of the Lig4 locus A. UCSC genome browser snapshot of the LIG4 locus and surrounding genes. The Top track shows relative genomic scale, and gene location. Genes are represented as thick dark blue lines for coding exons, and thin lines for introns. Bottom tracks represent ATAC-seq data from double positive thymocytes (immgen) and E15 forebrain (ENCODE), with MACs2 peak calling above the tracks. B. HiGlass snapshots of Hi-C data from the 4D nucleosome project (https://4dnucleome.org/), which shows data derived from double positive thymocytes (top) and E15 forebrain (bottom). Genes are separated by strand, with forward genes in shown on blue and reverse genes in red. C. Cross-tissue ATAC-seq analysis, derived from the immgen consortium, showing the LIG4 region. The heatmap to right shows Lig4 expression, with red being highest and blue being lowest. On top, thin bars are untranslated regions, thick bars are translated exons and narrow lines are introns.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-5718046/v1/3eaba444838b5cdc07659bbf.png"},{"id":73021942,"identity":"9dfed673-000b-41c6-8c6f-2342cd7cce8d","added_by":"auto","created_at":"2025-01-06 04:01:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":602862,"visible":true,"origin":"","legend":"\u003cp\u003eCreation and initial phenotyping of Lig4-iRE-knockout mice A. UCSC genome browser snapshots, as in figure 2A. The blue highlight shows the Lig4-iRE deletion region. Bottom BLAT track shows sequenced region (thick bars). B. Whole thymus, spleen, brain, colon, eye, heart, liver, and pancreas were analyzed for Lig4 RNA versus B2M control RNA. Dots are biological replicates, and statistics are a T test. ** p \u0026lt; 0.01, *** p \u0026lt; 0.0001 C. Whole thymic extracts were analyzed for Ligase IV protein from WT mice and mice with intronic deletion. Each lane is a different mouse. D. Absolute numbers of indicated thymocytes in 9-week males. Student’s T test P values are indicated above bars. Representative flow plots are shown in Figure S3B. E. Diagram showing competitive bone marrow chimera experiment. F. Flow cytometry of mixed bone marrow chimera experiments. Dots are biological replicates and statistics are a T test, * p \u0026lt; 0.05. Representative flow cytometry dot plots are shown in figure S3C.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-5718046/v1/3940c889b4606acea3b59f10.png"},{"id":73021945,"identity":"d2f9f6c5-ce82-4b5d-b299-da21e09b2969","added_by":"auto","created_at":"2025-01-06 04:01:45","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":300645,"visible":true,"origin":"","legend":"\u003cp\u003eT cell receptor beta recombination in DN cells A. DN thymocytes were processed for TCRβ repertoire and plotted via multi-dimensional scaling (MDS) analysis with K-means clustering. Each point represents a biological replicate, and relative genotypes of Lig4-iRE or WT cells are labeled next to the data points. B. Analysis of Vβ use from DN cells. Dots are biological replicates, and statistics are a T test. * p \u0026lt; 0.01. C. Jβ use. D. Average length of nucleotides added to the TCRβ V(D)J junctions in biological independent replicates. Statistics are a T test. * p \u0026lt; 0.01 E. Distribution of CDR3 lengths in WT versus Lig4-iRE DN cells.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-5718046/v1/1eeef1674a77ffd55ceaf747.png"},{"id":73021947,"identity":"1775979d-5263-49af-9a8e-32386975a92b","added_by":"auto","created_at":"2025-01-06 04:01:45","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":368102,"visible":true,"origin":"","legend":"\u003cp\u003eResponse to exogenous radiation in of Lig4-iRE-knockout mice A. Schematic illustration of whole-body radiation experimental set up. Animals were given 0, 2, or 6 Gy doses of whole-body X-ray radiation, and analyzed at 4 hours, or up to two weeks. B. Lineage negative (Lin-) and double negative (Lin-CD4-CD8-) thymocytes were stained with Annexin V and a Ghost Dye. Quantification of thymocyte death is shown on right. P values are Student’s T test, and significance values are shown on top.\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-5718046/v1/3aabb309734252d82d0de97c.png"},{"id":73021949,"identity":"9636a534-a936-4ecc-8887-75ef3b1fef62","added_by":"auto","created_at":"2025-01-06 04:01:45","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":447704,"visible":true,"origin":"","legend":"\u003cp\u003eB cell phenotype of Lig4-iRE-knockout mice A. Sorted bone marrow populations were analyzed for Lig4 RNA versus B2M control RNA. Dots are biological replicates. B. Absolute percentages of indicated Hardy fractions in 9-week males. Each dot is an individual replicate, and all differences are non-significant by a student’s T test. C. Diagram showing competitive bone marrow chimera experiment. D. Flow cytometry of mixed bone marrow chimera experiments. Dots are biological replicates and statistics are a T test. Representative flow cytometry dot plots are shown in figure S6A. E. In vitro class switch assay. Isolated B cells were cultured for four days with LPS + IL-4, and class switching to IgG1 was determined by flow cytometry.\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-5718046/v1/0d2ad4b5315b039e431b2cf7.png"},{"id":73022531,"identity":"ffcdb26c-c07e-4493-bd64-110b3e58c047","added_by":"auto","created_at":"2025-01-06 04:09:45","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":441865,"visible":true,"origin":"","legend":"\u003cp\u003eThe transcription factors HEB\u0026amp;E2A governs Lig4 transcription A. Integrated genome viewer (IGV) snapshot that shows published thymocyte ChIP-seq data, which was processed via the ChIP-Atlas web portal (SRX numbers are unique identifiers for data origination and publication). On the top is genomic localization and gene position, with thin bars being untranslated regions, and thick bars representing the translated exon. The middle histograms show published ChIP-seq data, with each histogram scaling from minimum to maximum. A combined peak track showing all ChIP-seq follows. The bottom track shows vertebrate conservation, which was derived from the UCSC genome browser conservation data, and above blue represents conserved sequences. B. Zoom-in of the deleted region. Multi-species conservation is indicated with select species that are used to produce antibodies listed in red. C. Data shows gene expression taken from D’Cruz et al, N immunology 2010, which evaluated sorted double positive thymocyte gene expression in CD4cre animals (controls), or also with E2A flox/flox and HEBFlox/flox D. Lig4 probe expression in all genotypes from D’Cruz et al.\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-5718046/v1/6c79f67faa668b71a0245e38.png"},{"id":90711763,"identity":"8f4819f8-7fad-494f-a304-f6fafac0dee5","added_by":"auto","created_at":"2025-09-06 07:08:51","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1901879,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ManuscriptBody.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5718046/v1_covered_998ec4ce-280f-496c-bfb5-371ca7209e4c.pdf"},{"id":73022530,"identity":"93efb7de-3ffd-477b-a2d2-d82094f8c14b","added_by":"auto","created_at":"2025-01-06 04:09:45","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1536670,"visible":true,"origin":"","legend":"Supplemental Figures","description":"","filename":"SupFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5718046/v1/15a6a6a36cb4177144c93d56.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.\nThe authors declare that they have no competing interests","formattedTitle":"Transcriptional regulation of the non-homologous end joining gene Ligase IV by an intronic regulatory element directs thymocyte development","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"genes-and-immunity","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"genes","sideBox":"Learn more about [Genes \u0026 Immunity](http://www.nature.com/gene/)","snPcode":"41435","submissionUrl":"https://mts-gene.nature.com/cgi-bin/main.plex","title":"Genes \u0026 Immunity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Non-homologous end joining, gene regulation, V(D)J recombination, cis-regulatory element, Ligase IV, double-strand break response","lastPublishedDoi":"10.21203/rs.3.rs-5718046/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5718046/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Double-strand breaks represent the most dangerous form of DNA damage, and in resting cells, these breaks are sealed via the non-homologous end joining (NHEJ) factor Ligase IV (LIG4). Excessive NHEJ may be genotoxic, necessitating multiple mechanisms to control NHEJ activity. However, a clear mechanism of transcriptional control for them has not yet been identified. Here, we examine mechanisms governing Lig4 transcription in mammals, finding that most tissues maintain very low levels of LIG4 production. Select tissues upregulate LIG4, employing different strategies for genomic regulation. In developing lymphocytes, the Lig4 locus is devoid of long-range chromatin contacts; instead, its expression and role in immune development depend upon a promoter-proximal intronic regulatory element. Deletion of the Lig4 intronic regulatory element results in thymocyte-specific loss of Lig4 upregulation, defects in lymphocyte development and altered antigen receptor rearrangement. Our findings show the NHEJ gene, Lig4, is transcriptionally controlled to support stage-specific function concurrent with programmed DSBs. Moreover, we provide an example of how DNA cis-regulatory elements very close to a promoter can have substantial transcriptional effects.","manuscriptTitle":"Transcriptional regulation of the non-homologous end joining gene Ligase IV by an intronic regulatory element directs thymocyte development","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-06 04:01:40","doi":"10.21203/rs.3.rs-5718046/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-03-04T16:47:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-02-26T22:54:19+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-02-23T12:37:00+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-02-16T09:48:55+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-02-12T18:20:05+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-01-27T17:00:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-12-30T17:23:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Genes \u0026 Immunity","date":"2024-12-26T21:42:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-12-26T21:42:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"genes-and-immunity","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"genes","sideBox":"Learn more about [Genes \u0026 Immunity](http://www.nature.com/gene/)","snPcode":"41435","submissionUrl":"https://mts-gene.nature.com/cgi-bin/main.plex","title":"Genes \u0026 Immunity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c36d2d74-1641-44cf-a39c-bf24487ef677","owner":[],"postedDate":"January 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":42177659,"name":"Biological sciences/Immunology/Immunogenetics"},{"id":42177660,"name":"Biological sciences/Genetics/Gene regulation"},{"id":42177661,"name":"Biological sciences/Immunology/Gene regulation in immune cells"},{"id":42177662,"name":"Biological sciences/Immunology/Lymphocytes"}],"tags":[],"updatedAt":"2025-09-06T07:08:37+00:00","versionOfRecord":{"articleIdentity":"rs-5718046","link":"https://doi.org/10.1038/s41435-025-00353-3","journal":{"identity":"genes-and-immunity","isVorOnly":false,"title":"Genes \u0026 Immunity"},"publishedOn":"2025-09-05 04:00:00","publishedOnDateReadable":"September 5th, 2025"},"versionCreatedAt":"2025-01-06 04:01:40","video":"","vorDoi":"10.1038/s41435-025-00353-3","vorDoiUrl":"https://doi.org/10.1038/s41435-025-00353-3","workflowStages":[]},"version":"v1","identity":"rs-5718046","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5718046","identity":"rs-5718046","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}