Loss of BAF (mSWI/SNF) Complexes Causes Global Transcriptional and Chromatin State Changes in Forebrain Development
Loss of BAF (mSWI/SNF) Complexes Causes Global Transcriptional and Chromatin State Changes in Forebrain Development
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DOI：
10.1016/j.celrep.2015.10.046
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发表时间：
2015-12-01
期刊：
影响因子：
8.8
通讯作者：
Tuoc, Tran
中科院分区：
文献类型：
--
作者：
Narayanan, Ramanathan;Pirouz, Mehdi;Tuoc, Tran
BAF（Brg/Brm相关因子）复合物在发育中起着重要作用，并与选定基因组位点的染色质可塑性有关。然而，由于缺乏完全缺乏BAF复合物的突变体，对它们在发育和染色质重塑中的作用的充分理解受到阻碍。在这里，我们报告说，BAF 155/BAF 170双条件性敲除（dcKO）小鼠的损失消除了所有已知的BAF亚基，导致在一个整体减少活跃的染色质标记（H3 K9 Ac），抑制性标记（H3 K27 me 2/3）的全球增加，基因表达下调。我们证明BAF复合物与H3 K27脱甲基酶（JMJD 3和UTX）相互作用并增强其活性。重要的是，BAF复合物对于前脑发育是不可或缺的，包括神经祖细胞的增殖、分化和细胞存活。我们的研究结果揭示了一个由BAF复合物介导的分子机制，该机制控制着发育中的全球转录程序和染色质状态。
BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knockout (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and downregulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3 and UTX) and potentiate their activity. Importantly, BAF complexes are indispensable for forebrain development, including proliferation, differentiation, and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls the global transcriptional program and chromatin state in development.