Epigenetics and Stem Cell Biology Laboratory, National Institutes of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Sci Adv. 2024 Mar;10(9):eadj5107. doi: 10.1126/sciadv.adj5107. Epub 2024 Mar 1.
Cell fate decisions are achieved with gene expression changes driven by lineage-specific transcription factors (TFs). These TFs depend on chromatin remodelers including the Brahma-related gene 1 (BRG1)-associated factor (BAF) complex to activate target genes. BAF complex subunits are essential for development and frequently mutated in cancer. Thus, interrogating how BAF complexes contribute to cell fate decisions is critical for human health. We examined the requirement for the catalytic BAF subunit BRG1 in neural progenitor cell (NPC) specification from human embryonic stem cells. During the earliest stages of differentiation, BRG1 was required to establish chromatin accessibility at neuroectoderm-specific enhancers. Depletion of BRG1 dorsalized NPCs and promoted precocious neural crest specification and enhanced neuronal differentiation. These findings demonstrate that BRG1 mediates NPC specification by ensuring proper expression of lineage-specific TFs and appropriate activation of their transcriptional programs.
细胞命运的决定是通过由谱系特异性转录因子(TFs)驱动的基因表达变化来实现的。这些 TF 依赖于染色质重塑因子,包括 Brm 相关基因 1(BRG1)相关因子(BAF)复合物,以激活靶基因。BAF 复合物亚基对于发育是必不可少的,并且在癌症中经常发生突变。因此,研究 BAF 复合物如何有助于细胞命运的决定对于人类健康至关重要。我们研究了催化 BAF 亚基 BRG1 在人胚胎干细胞向神经祖细胞(NPC)分化过程中的作用。在分化的最早阶段,BRG1 需要在神经外胚层特异性增强子处建立染色质可及性。BRG1 的耗竭使 NPC 向背侧化,促进了神经嵴前体细胞的特化,并增强了神经元的分化。这些发现表明,BRG1 通过确保谱系特异性 TF 的正确表达以及它们的转录程序的适当激活来介导 NPC 的特化。