Open Access
Open access
Nucleic Acids Research, volume 51, issue 21, pages 11634-11651

BRD9-mediated control of the TGF-β/Activin/Nodal pathway regulates self-renewal and differentiation of human embryonic stem cells and progression of cancer cells

Xuepeng Wang 1
Chengcheng Song 2
Ying Ye 3
Yashi Gu 4
Xuemei Li 5
Peixin Chen 3
Dongliang Leng 2
Jing Xiao 2
Hao Wu 3
SiSi Xie 4
Weiwei Liu 2
Qi Zhao 2
Di Chen 4
Xi Chen 6
Qiang Wu 1, 7
Guokai Chen 2
Wensheng Zhang 3, 5, 8
Show full list: 17 authors
Publication typeJournal Article
Publication date2023-10-23
scimago Q1
wos Q1
SJR7.048
CiteScore27.1
Impact factor16.6
ISSN03051048, 13624962
Genetics
Abstract

Bromodomain-containing protein 9 (BRD9) is a specific subunit of the non-canonical SWI/SNF (ncBAF) chromatin-remodeling complex, whose function in human embryonic stem cells (hESCs) remains unclear. 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-β, Activin A or WNT3A rescues the differentiation defects caused by BRD9 loss. Mechanistically, BRD9 forms a complex with BRD4, SMAD2/3, β-CATENIN and P300, which regulates the expression of pluripotency genes and the activity of TGF-β/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-β/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.

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