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Here, we demonstrate that impaired BRD9 function reduces the self-renewal capacity of hESCs and alters their differentiation potential. Specifically, BRD9 depletion inhibits meso-endoderm differentiation while promoting neural ectoderm differentiation. Notably, supplementation of NODAL, TGF-\u03b2, Activin A or WNT3A rescues the differentiation defects caused by BRD9 loss. Mechanistically, BRD9 forms a complex with BRD4, SMAD2\/3, \u03b2-CATENIN and P300, which regulates the expression of pluripotency genes and the activity of TGF-\u03b2\/Nodal\/Activin and Wnt signaling pathways. This is achieved by regulating the deposition of H3K27ac on associated genes, thus maintaining and directing hESC differentiation. BRD9-mediated regulation of the TGF-\u03b2\/Activin\/Nodal pathway is also demonstrated in the development of pancreatic and breast cancer cells. In summary, our study highlights the crucial role of BRD9 in the regulation of hESC self-renewal and differentiation, as well as its participation in the progression of pancreatic and breast cancers.<\/jats:p>","DOI":"10.1093\/nar\/gkad907","type":"journal-article","created":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T09:54:16Z","timestamp":1698054856000},"page":"11634-11651","source":"Crossref","is-referenced-by-count":28,"title":["BRD9-mediated control of the TGF-\u03b2\/Activin\/Nodal pathway regulates self-renewal and differentiation of human embryonic stem cells and progression of cancer cells"],"prefix":"10.1093","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1905-778X","authenticated-orcid":false,"given":"Xuepeng","family":"Wang","sequence":"first","affiliation":[{"name":"The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology , Taipa , Macao SAR 999078,\u00a0 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengcheng","family":"Song","sequence":"additional","affiliation":[{"name":"Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau , Taipa , Macao SAR 999078,\u00a0 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Ye","sequence":"additional","affiliation":[{"name":"Medical College of Soochow University , Suzhou 215123 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashi","family":"Gu","sequence":"additional","affiliation":[{"name":"Zhejiang University\u2013University of Edinburgh Institute (ZJE), Zhejiang University School of Medicine, Zhejiang University , Haining\u00a0 314400 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Li","sequence":"additional","affiliation":[{"name":"Peninsula Cancer Research Center, School of Basic Medical Sciences, Binzhou Medical University , Yantai\u00a0 264003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peixin","family":"Chen","sequence":"additional","affiliation":[{"name":"Medical College of Soochow University , Suzhou 215123 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongliang","family":"Leng","sequence":"additional","affiliation":[{"name":"Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau , Taipa , Macao SAR 999078,\u00a0 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xiao","sequence":"additional","affiliation":[{"name":"Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau , Taipa , Macao SAR 999078,\u00a0 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"Medical College of Soochow University , Suzhou 215123 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sisi","family":"Xie","sequence":"additional","affiliation":[{"name":"Zhejiang University\u2013University of Edinburgh Institute (ZJE), Zhejiang University School of Medicine, Zhejiang University , Haining\u00a0 314400 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau , Taipa , Macao SAR 999078,\u00a0 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau , Taipa , Macao SAR 999078,\u00a0 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Technology , Taipa , Macao SAR 999078,\u00a0 China"},{"name":"The Precision Regenerative Medicine Centre, Macau University of Science and Technology , Taipa, Macao SAR 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0921-8244","authenticated-orcid":false,"given":"Guokai","family":"Chen","sequence":"additional","affiliation":[{"name":"Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau , Taipa , Macao SAR 999078,\u00a0 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6876-3173","authenticated-orcid":false,"given":"Wensheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Medical College of Soochow University , Suzhou 215123 , China"},{"name":"Peninsula Cancer Research Center, School of Basic Medical Sciences, Binzhou Medical University , Yantai\u00a0 264003 , China"},{"name":"School of Life Sciences and Medicine, Shandong University of Technology , Zibo, 255049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,23]]},"reference":[{"key":"2023112805220731500_B1","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1146\/annurev-cellbio-100913-013116","article-title":"The nature of embryonic stem cells","volume":"30","author":"Martello","year":"2014","journal-title":"Annu. 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