A study of the entire multi-subunit BAF (mSWI/SNF) complex loss in global epigenetic regulation of cerebral cortex development

大脑皮层发育全局表观遗传调控中整个多亚基 BAF (mSWI/SNF) 复合体缺失的研究

• 批准号: 290354032
• 负责人: Dr. Tran Cong Tuoc, Ph.D.
• 金额: --
• 依托单位: Abteilung für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290354032?language=en
• 关键词: study; entire; multi; subunit; BAF

The diversity of projection neurons in cerebral cortex is generated from pluripotent ventricular radial glial progenitors (vRGs). The chromatin and epigenetic regulation are essential for appropriate and timely gene expression in systems such as embryonic stem cells.However, such mechanism assumed to coordinate the activation or repression of gene expression programs during the acquisition of distinct neural cell fates of vRGs in cortical development, are largely unknown. In this proposal, we investigate the roles of multi-subunit chromatin remodeling BAF complexes in cortical development. At least 15 subunits assemble combinatorially to generate an extensive diversity of complexes with specialized functions in specific tissues. A loss of one BAF subunit often affects the local chromatin structure and a specific transcriptional program. Nevertheless, thus far a full understanding of BAF complexes in development is not possible due to the lack of animal mutants for the entire multi-subunit BAF complexes. Recently, we generated cortex-specific double conditional knock-out (dcKO) mice for BAF155 and BAF170 subunits. Strikingly, the loss of BAF155 and BAF170 subunits in dcKO mutants eliminates all known BAF subunits in cortical tissues and primary neurons. In addition, the loss of BAF complex resulted in a global increase in repressive marks with a concurrent overall reduction in active marks of chromatins. The generated dcKO mutants thus provide a novel powerful tool to investigate the roles of entire BAF complexes in cortical development. The main aim of this project is to examine the roles of chromatin remodeling in corticogenesis, with a focus on how chromatin regulation by BAF complex controls neural gene expression programs during cortical neurogenesis, using a combination of genetic manipulation, genomic and proteomic approaches.

大脑皮层投射神经元的多样性是由多能心室放射状胶质祖细胞（vRG）产生的。染色质和表观遗传调控对于胚胎干细胞等系统中适当和及时的基因表达至关重要。然而，在皮层发育中获得 vRG 的不同神经细胞命运期间，这种被认为协调基因表达程序的激活或抑制的机制在很大程度上是未知的。在本提案中，我们研究了多亚基染色质重塑 BAF 复合物在皮质发育中的作用。至少 15 个亚基组合组装，产生广泛多样性的复合物，在特定组织中具有特殊功能。一个 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，由于缺乏整个多亚基 BAF 复合物的动物突变体，迄今为止不可能完全了解 BAF 复合物的发育过程。最近，我们生成了 BAF155 和 BAF170 亚基的皮质特异性双条件敲除 (dcKO) 小鼠。引人注目的是，dcKO 突变体中 BAF155 和 BAF170 亚基的丢失消除了皮质组织和初级神经元中所有已知的 BAF 亚基。此外，BAF 复合物的丢失导致抑制标记的整体增加，同时染色质活性标记的总体减少。因此，生成的 dcKO 突变体为研究整个 BAF 复合物在皮质发育中的作用提供了一种新颖的强大工具。该项目的主要目的是研究染色质重塑在皮质生成中的作用，重点是结合遗传操作、基因组和蛋白质组学方法，研究 BAF 复合物对染色质的调节如何在皮质神经发生过程中控制神经基因表达程序。