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

作者：Xuepeng Wang, Chengcheng Song, Ying Ye, Yashi Gu, Xuemei Li, Peixin Chen, Dongliang Leng, Jing Xiao, Hao Wu, Sisi Xie, Weiwei Liu, Qi Zhao, Di Chen, Xi Chen, Qiang Wu, Guokai Chen, Wensheng Zhang · 发表于：Nucleic Acids Research · 年份：2023 · DOI：10.1093/nar/gkad907 · 被引用次数：29 · 研究领域：Protein Degradation and Inhibitors、Chromatin Remodeling and Cancer、Genomics and Chromatin Dynamics

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.