State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Nucleic Acids Res. 2018 Mar 16;46(5):2290-2307. doi: 10.1093/nar/gkx1295.
Defects in neurogenesis alter brain circuit formations and may lead to neurodevelopmental disorders such as autism and schizophrenia. Histone H2A.z, a variant of histone H2A, plays critical roles in chromatin structure and epigenetic regulation, but its function and mechanism in brain development remain largely unknown. Here, we find that the deletion of H2A.z results in enhanced proliferation of neural progenitors but reduced neuronal differentiation. In addition, neurons in H2A.z knockout mice exhibit abnormal dendrites during brain development. Furthermore, H2A.zcKO mice exhibit serial behavioral deficits, such as decreased exploratory activity and impaired learning and memory. Mechanistically, H2A.z regulates embryonic neurogenesis by targeting Nkx2-4 through interaction with Setd2, thereby promoting H3K36me3 modification to activate the transcription of Nkx2-4. Furthermore, enforced expression of Nkx2-4 can rescue the defective neurogenesis in the H2A.z-knockdown embryonic brain. Together, our findings implicate the epigenetic regulation by H2A.z in embryonic neurogenesis and provide a framework for understanding how disruption in the H2A.z gene may contribute to neurological disorders.
神经发生缺陷会改变大脑回路的形成，并可能导致神经发育障碍，如自闭症和精神分裂症。组蛋白 H2A.z 是组蛋白 H2A 的一种变体，在染色质结构和表观遗传调控中发挥着关键作用，但它在大脑发育中的功能和机制在很大程度上仍不清楚。在这里，我们发现 H2A.z 的缺失会导致神经祖细胞的增殖增强，但神经元分化减少。此外，H2A.z 敲除小鼠的神经元在大脑发育过程中表现出异常的树突。此外，H2A.zcKO 小鼠表现出一系列行为缺陷，如探索活动减少和学习记忆受损。在机制上，H2A.z 通过与 Setd2 相互作用，靶向 Nkx2-4，从而促进 H3K36me3 修饰，激活 Nkx2-4 的转录，调节胚胎神经发生。此外，强制表达 Nkx2-4 可以挽救 H2A.z 敲低胚胎大脑中神经发生的缺陷。总之，我们的研究结果表明 H2A.z 的表观遗传调控在胚胎神经发生中起作用，并为理解 H2A.z 基因的破坏如何导致神经障碍提供了一个框架。
