Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
Sci Rep. 2022 Sep 17;12(1):15636. doi: 10.1038/s41598-022-19654-y.
Mutations in the chromodomain helicase DNA binding protein 2 (CHD2) gene are associated with neurodevelopmental disorders. However, mechanisms by which CHD2 regulates human brain development remain largely uncharacterized. Here, we used a human embryonic stem cell model of cortical interneuron (hcIN) development to elucidate its roles in this process. We identified genome-wide CHD2 binding profiles during hcIN differentiation, defining direct CHD2 targets related to neurogenesis in hcIN progenitors and to neuronal function in hcINs. CHD2 bound sites were frequently coenriched with histone H3 lysine 27 acetylation (H3K27ac) and associated with high gene expression, indicating roles for CHD2 in promoting gene expression during hcIN development. Binding sites for different classes of transcription factors were enriched at CHD2 bound regions during differentiation, suggesting transcription factors that may cooperatively regulate stage-specific gene expression with CHD2. We also demonstrated that CHD2 haploinsufficiency altered CHD2 and H3K27ac coenrichment on chromatin and expression of associated genes, decreasing acetylation and expression of cell cycle genes while increasing acetylation and expression of neuronal genes, to cause precocious differentiation. Together, these data describe CHD2 direct targets and mechanisms by which CHD2 prevents precocious hcIN differentiation, which are likely to be disrupted by pathogenic CHD2 mutation to cause neurodevelopmental disorders.
染色质解旋酶 DNA 结合蛋白 2 (CHD2) 基因突变与神经发育障碍有关。然而,CHD2 调节人类大脑发育的机制在很大程度上仍未被阐明。在这里,我们使用皮质中间神经元 (hcIN) 发育的人类胚胎干细胞模型来阐明其在这个过程中的作用。我们在 hcIN 分化过程中确定了全基因组 CHD2 结合谱,确定了与 hcIN 祖细胞中的神经发生以及 hcIN 中的神经元功能直接相关的 CHD2 靶标。CHD2 结合位点经常与组蛋白 H3 赖氨酸 27 乙酰化 (H3K27ac) 共富集,并与高基因表达相关,表明 CHD2 在 hcIN 发育过程中促进基因表达的作用。在分化过程中,不同类别的转录因子的结合位点在 CHD2 结合区域富集,表明转录因子可能与 CHD2 共同调节特定阶段的基因表达。我们还证明 CHD2 杂合不足改变了染色质上的 CHD2 和 H3K27ac 共富集以及相关基因的表达,降低了细胞周期基因的乙酰化和表达,同时增加了神经元基因的乙酰化和表达,导致过早分化。总之,这些数据描述了 CHD2 的直接靶标和 CHD2 防止 hcIN 过早分化的机制,这些机制可能因致病性 CHD2 突变而被破坏,导致神经发育障碍。