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.
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.
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DOI：
10.1093/nar/gkad907
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发表时间：
2023-11-27
影响因子：
14.9
通讯作者：
中科院分区：
文献类型：
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含溴结构域蛋白9（Bromodomain-containing protein 9，BRD 9）是非典型SWI/SNF（ncBAF）染色质重塑复合物的一个特异性亚基，其在人胚胎干细胞（human embryonic stem cells，hESC）中的功能尚不清楚。在这里，我们证明了受损的BRD 9功能降低了hESC的自我更新能力，并改变了它们的分化潜力。具体地，BRD 9耗尽抑制中-内胚层分化，同时促进神经外胚层分化。值得注意的是，NODAL、TGF-β、激活素A或WNT 3A的补充挽救了由BRD 9损失引起的分化缺陷。在机制上，BRD 9与BRD 4、SMAD 2/3、β-连环蛋白和P300形成复合物，其调节多能性基因的表达以及TGF-β/Nodal/Activin和Wnt信号通路的活性。这是通过调节H3 K27 ac在相关基因上的沉积来实现的，从而维持和指导hESC分化。BRD 9介导的TGF-β/激活素/Nodal途径的调节也在胰腺癌和乳腺癌细胞的发展中得到证实。总之，我们的研究强调了BRD 9在调节hESC自我更新和分化中的关键作用，以及其参与胰腺癌和乳腺癌的进展。
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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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
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通讯作者：
Hargreaves DC
影响因子：
5.2
作者：
Bevill, Samantha M.;Olivares-Quintero, Jose F.;Johnson, Gary L.
通讯作者：
Johnson, Gary L.
影响因子：
4
作者：
Diekmann, Ulf;Lenzen, Sigurd;Naujok, Ortwin
通讯作者：
Naujok, Ortwin
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK