Oligodendrocyte precursor differentiation and survival requires chromatin remodeling by Chd7 and Chd8 [ChIP-seq]

Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest Autism Spectrum Disorder (ASD) high-risk associated genes. Here, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin-binding profile combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects non-proliferative OPCs from apoptosis by chromatin-closing and transcriptional repression of p53. Furthermore, Chd7 controls OPC differentiation through chromatin-opening and transcriptional activation of key regulators, including Sox10, Nkx2.2 and Gpr17. Chd7 is however dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD-risk associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease. Overall design: Chd7 & Chd8 ChIP-seq from in vivo mouse O4+ cells少突胶质前体细胞（Oligodendrocyte precursor cells, OPCs）是成体脑中主要的增殖细胞群，其增殖-分化平衡失调会导致胶质瘤形成或适应性（再）髓鞘形成缺陷。少突胶质前体细胞的分化需要涉及染色质重塑的显著遗传重编程。越来越多的证据表明，染色质重塑因子（chromatin remodelers）在正常发育过程中发挥关键作用，其突变与神经发育缺陷密切相关：其中CHD7单倍剂量不足是CHARGE综合征的致病原因，而CHD8是自闭症谱系障碍（Autism Spectrum Disorder, ASD）最高危的相关基因之一。本研究报道了染色质重塑因子Chd7与Chd8在少突胶质前体细胞中尚未被阐明的功能。通过整合Chd7缺失的少突胶质前体细胞的染色质结合谱、转录组及染色质开放性分析数据，我们发现Chd7可通过染色质闭合与p53转录抑制，保护非增殖态少突胶质前体细胞免于凋亡。此外，Chd7可通过染色质开放与Sox10、Nkx2.2及Gpr17等关键调控因子的转录激活，调控少突胶质前体细胞的分化。然而，Chd7对于少突胶质细胞的发育阶段进展并非必需，这与Chd8的补偿性功能一致——该结论可通过二者共有的染色质结合谱与遗传互作得到佐证。最后，CHD7与CHD8在少突胶质前体细胞中结合了绝大多数自闭症谱系障碍风险相关基因，提示少突胶质系细胞参与了自闭症谱系障碍的神经发育缺陷。本研究结果因此为理解与调控CHD7和CHD8在正常发育及疾病中的功能提供了全新的研究方向。 总体实验设计：基于体内小鼠O4+细胞的Chd7与Chd8染色质免疫共沉淀测序（Chromatin Immunoprecipitation sequencing, ChIP-seq）分析。