Brain-specific deletion of histone variant H2A.z results in cortical neurogenesis defects and neurodevelopmental disorder

Abstract

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.

TIP60 acetylates H2AZ and regulates doxorubicin-induced DNA damage sensitivity throughRAD51transcription

“…Similar genome-wide studies have been done in yeast (Millar et al, 2006), while other reports in human cells are mainly on a single H2AZ regulated gene such as CCND1 (Dalvai et al, 2013a) or Notch target gene (Giaimo et al, 2018). Several groups also studied global changes in AcH2AZ and H2AZ in human cells but in different contexts such as cancer studies, stem cell differentiation, and in the transcriptional context (Dong et al, 2016;Hardy et al, 2009;Lashgari et al, 2017;Shen et al, 2017;Valdes-Mora et al, 2017;Valdes-Mora et al, 2012;Vardabasso et al, 2015). Nonetheless, when we integrate ChIP-seq data with RNA-seq, the conclusion that AcH2AZ is enriched on actively transcribed genes corroborates with other studies (Dalvai et al, 2013a;Giaimo et al, 2018;Hu et al, 2013;Valdes-Mora et al, 2017;Valdes-Mora et al, 2012).…”

H2A.Z-dependent and -independent recruitment of metabolic enzymes to chromatin required for histone modifications

“…H2A.Z is required for transcriptional memory in yeast where it is incorporated in newly deactivated INO1 at the nuclear periphery 27, 28 , and in hippocampal memory in mice, where it negatively controls fear memory through suppressing the expression of specific memory-activating genes 29 , and is necessary for neurogenesis and normal behavioral traits in mice 30 . As well established, memory is a function of epigenetics, wherein histone acetylation is an essential regulator, demonstrated by Mews et al 31 .…”

H2A.Z.1 crosstalk with H3K56-acetylation controls gliogenesis through the transcription of folate receptor

“…In our study, we demonstrated that histone variant H2A.Z.1 crosstalk with the recently demonstrated chromatin marker H3K56ac acts to regulate gliogenesis in the developing cortex. Recently, a related study demonstrated that H2A.Z.1 regulates embryonic neurogenesis ( 27 ). As for the embryonic cortex development, neurogenesis and gliogenesis are inextricably intertwined.…”

“…Consistent with these functions, H2A.Z.1 has been found to be located in the promoter regions of genes and is associated with other regulatory regions ( 24 , 25 ). Recently, H2A.Z.1 has been found to have specialized functions that regulate lineage commitment during cellular specification and regulated embryonic neurogenesis by targeting Nkx2-4 through interaction with Setd2 ( 26 , 27 ), which suggests that H2A.Z.1 may be necessary for the specification of NPCs in the central nervous system (CNS). As for the embryonic cortex development, neurogenesis and gliogenesis are inextricably intertwined.…”