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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:p>Transforming growth factor \u03b2 (TGF\u03b2) signaling pathways are integral for a plethora of biological processes. SMAD2 and SMAD3 are the principal transcriptional effectors of TGF\u03b2 superfamily ligands, yet quantitative, genome-wide mapping of their DNA-associated complexes under physiological contexts has remained limited due to the lack of specific, robust models. Here, we generated two versatile epitope\u2013tagged mouse models in which endogenous SMAD2 and SMAD3 proteins are globally tagged with hemagglutinin (HA) and podoplanin (PA) sequences, respectively, enabling high-fidelity profiling of SMAD2 and SMAD3 binding across tissues. To demonstrate the broad application of our models, we exemplified the usage of our lines in ovarian biology, where we defined the transcriptional programs downstream of GDF9, a key oocyte-derived ligand in folliculogenesis from the TGF\u03b2 superfamily. By integrating genomic and transcriptomic analyses, we identified direct genes induced by the GDF9-SMAD2\/3 axis and identified gene sets suppressed by this signaling cascade, highlighting a previously underappreciated role of GDF9 in attenuating competing pathways to ensure proper ovarian granulosa cell fate transitions. Short-term GDF9 stimulation shifts SMAD2\/3 cofactor recruitment toward lineage- and differentiation-associated transcription factors, without significant global changes in H3K27ac landscapes, indicating that GDF9 signals through targeted SMAD recruitment to preacetylated chromatin regions. Network analyses further demonstrated that GDF9-SMAD2\/3 direct targets align with luteinizing hormone-driven preovulatory signaling. Together, our study generated epitope-tagged mouse models that provide extensive and applicable in vivo genetic toolkits for tissue-specific dissection of TGF\u03b2 family signaling and reveal a comprehensive, direct transcriptional network through which GDF9 coordinates granulosa cell differentiation and follicular maturation.<\/jats:p>","DOI":"10.1073\/pnas.2600071123","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T19:02:15Z","timestamp":1774897335000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Versatile SMAD2 and SMAD3 epitope\u2013tagged mouse models for genomic profiling of TGF\u03b2 signaling: Uncovering GDF9\u2013SMAD2\/3 targets"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7198-2182","authenticated-orcid":false,"given":"Zian","family":"Liao","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine","place":["Houston"]},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine","place":["Houston"]},{"name":"Graduate Program of Genetics and Genomics, Baylor College of Medicine","place":["Houston"]},{"name":"Center for Drug Discovery, Baylor College of Medicine","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, University of Osaka","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3739-7163","authenticated-orcid":false,"given":"Keisuke","family":"Shimada","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, University of Osaka","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Nozawa","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine","place":["Houston"]},{"name":"Center for Drug Discovery, Baylor College of Medicine","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suni","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine","place":["Houston"]},{"name":"Center for Drug Discovery, Baylor College of Medicine","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9859-6217","authenticated-orcid":false,"given":"Masahito","family":"Ikawa","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, University of Osaka","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5660-6392","authenticated-orcid":false,"given":"Diana","family":"Monsivais","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine","place":["Houston"]},{"name":"Center for Drug Discovery, Baylor College of Medicine","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1445-8632","authenticated-orcid":false,"given":"Martin M.","family":"Matzuk","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine","place":["Houston"]},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine","place":["Houston"]},{"name":"Graduate Program of Genetics and Genomics, Baylor College of Medicine","place":["Houston"]},{"name":"Center for Drug Discovery, Baylor College of Medicine","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.07.036"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.6719.1"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13072-016-0100-6"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-022-08565-x"},{"key":"e_1_3_4_5_2","first-page":"383","volume-title":"The Physiology of Reproduction","author":"Rajkovic A.","year":"2006","unstructured":"A. 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Liao Data from \u201cVersatile SMAD2 and SMAD3 epitope-tagged mouse models for genome-wide profiling of TGF\u03b2 superfamily signaling: uncovering novel GDF9-SMAD2\/3 target genes.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE315433. Deposited 15 March 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2600071123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T19:03:02Z","timestamp":1774897382000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2600071123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":94,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2026,4,7]]}},"alternative-id":["10.1073\/pnas.2600071123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2600071123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]},"assertion":[{"value":"2026-01-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2600071123"}}