Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development
Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development
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DOI：
10.1080/15384101.2016.1160984
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发表时间：
2016-01-01
期刊：
影响因子：
4.3
通讯作者：
Tran Tuoc
中科院分区：
文献类型：
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作者：
Huong Nguyen;Sokpor, Godwin;Tran Tuoc
多亚基染色质重塑SWI/SNF（Brg/Brm相关因子的BAF）复合物在发育中起重要作用。研究表明，单个BAF亚基的丢失通常会影响局部染色质结构和特定的转录程序。然而，我们并不完全了解BAF复合物在发育中的功能，因为没有动物突变体被工程改造为缺乏完整的多亚基BAF复合物。重要的是，我们最近报道了小鼠BAF 155和BAF 170核心亚基的双条件性敲除（dcKO）消除了发育中皮质中其他BAF亚基的存在。所产生的dcKO突变体提供了一种新的和强大的工具，用于调查整个BAF复合物如何影响皮质发育。使用该模型，我们发现BAF复合物通过直接调节H3K27脱甲基酶Utx和Jmjd3的酶活性来全局控制关键异染色质标记H3K27me2和-3。在这里，我们提出了进一步的见解如何BAF 155和BAF 170核心亚基的支架能力保持稳定的BAF复合物在前脑和整个胚胎发育过程中。此外，我们表明，在上述模型中的BAF复合物的损失上调H3K27me3和损害前脑发育和胚胎发生。这些发现提高了我们对表观遗传机制及其调控的染色质重塑SWI/SNF复合物，控制胚胎发育的理解。
The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.