Trends in Cell Biology
Volume 30, Issue 11, November 2020, Pages 869-880
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Review
Histone Variants and Histone Modifications in Neurogenesis

https://doi.org/10.1016/j.tcb.2020.09.003Get rights and content

Highlights

  • Mammalian neurogenesis is a dynamically regulated process with diverse factors. Epigenetic mechanisms, including histone variants and histone modifications, are involved in the expression of many genes to regulate central nervous system (CNS) dynamics.

  • Histone variants are nonallelic isoforms of core histones that incorporate into nucleosomes and regulate the dynamic changes necessary for neurogenesis.

  • Histone modifications can be dynamically regulated by sets of enzymes that act as epigenetic marks to support cell fate decisions and ensure robust embryonic neurogenesis.

  • The interactions of histone variants and histone modifications are typically characterized in chromatin states that have important roles in the memory and switching of gene expression states during brain development.

  • Hi-C-based high-throughput chromatin conformation capture techniques provide important insights into 3D genome architecture. Multiple factors, such as A/B compartment changes, heterochromatin organization, and enhancer–promoter interactions, affect chromatin interaction dynamics in neuronal development.

During embryonic brain development, neurogenesis requires the orchestration of gene expression to regulate neural stem cell (NSC) fate specification. Epigenetic regulation with specific emphasis on the modes of histone variants and histone post-translational modifications are involved in interactive gene regulation of central nervous system (CNS) development. Here, we provide a broad overview of the regulatory system of histone variants and histone modifications that have been linked to neurogenesis and diseases. We also review the crosstalk between different histone modifications and discuss how the 3D genome affects cell fate dynamics during brain development. Understanding the mechanisms of epigenetic regulation in neurogenesis has shifted the paradigm from single gene regulation to synergistic interactions to ensure healthy embryonic neurogenesis.

Section snippets

Histone Variants and Histone Modifications Are Critical for the Dynamic Modulation of Neurogenesis

In eukaryotes, nucleosomes form the basic repeating units of chromatin and comprise core histones (H2A, H2B, H3, and H4). The nucleosomes provide functional complexity via the incorporation of histone variants, which in turn regulate chromatin architecture and gene expression. Histone variants contribute to extending the information potential of the genetic code. They also regulate normal brain function, and other forms of histone modifications have been linked to neurogenesis and neural

Histone Variants in Neurogenesis

Histone variants are structural components of chromatin; they are deposited onto chromatin by specific histone chaperones and interact with other chromatin modifiers (Table 1) [7,8]. Replacing canonical histones with histone variants affects the stability of nucleosomes and contributes to the production of functional chromatin domains [9]. Here, we mainly focus on variants of the H2A family and H3 family, which participate in the regulation of development (Figure 1).

The histone H2A family has

Histone Modifications in Neurogenesis

While histone variants affect neurogenesis, histone modifications, such as histone methylation, acetylation, phosphorylation, ubiquitination, crotonylation, and glycosylation, also directly or indirectly affect neurodevelopmental processes through different mechanisms. Abnormal histone modifications cause a series of neurological diseases and seriously endanger human health. Common histone modifications include methylation, acetylation, phosphorylation, and ubiquitination. Lysine (Lys or K) and

Interactions between Histone Modification and other Epigenetic Modifications

In the earlier sections, we described the different types of histone variant and histone modification in neurodevelopment. In terms of regulatory functions, these epigenetic mechanisms are seldom isolated but interact. We take H3K36me3, an important histone modification described earlier, as an example.

In the section on histone variants, we mentioned that H2A.Z regulates the differentiation of NPCs into neurons by targeting the Nkx2-4 promoter through interaction with H3K36me3

Dynamic Regulation of the 3D Genome in Neurogenesis

Genome architecture has a key role in gene transcription regulation and neural development. As sequencing-based technologies have developed, 3D genome studies have revealed high-order chromatin structures, including A/B compartments, topologically associated domains (TADs), and chromatin loops (Box 1) [6]. What is the role of 3D genomic organization in neural development? Chromatin dynamic changes are crucial in cell fate commitment. Recent studies showed chromatin global compaction during

Histone Dysregulation in Neurological Disorders

Mutations in histone variants are associated with various neurological disorders. For example, mutations in macroH2A have been identified as causing intellectual disability syndrome and Liebenberg syndrome, which is characterized by microcephaly and limb malformations [69]. In addition, mutations in H2BC13 and H2BC21 are associated with intellectual disability, which causes delayed development and intellectual disability [70]. Genetic variations of histone variant H4-16 are associated with

Concluding Remarks and Future Perspectives

Recently, epigenetic factors were found to be increasingly involved in modulating neurogenesis and the pathogenesis of neurodevelopmental disorders. There is now an urgent need to reveal how histone variants and modifications, two main parts of epigenetic factors, affect neurogenesis.

Among the various histone variants, H2A.Z and H3.3 are closely related to neurogenesis. H2A.Z and H3.3 separately recruit histone-modifying enzymes to regulate the transcriptional activity of downstream

Acknowledgments

This work was supported by grants from the CAS Strategic Priority Research Program (XDA16020602), the National Key R&D Program of China (2019YFA0110300), the National Natural Science Foundation of China (81825006, 31730033 and 31621004), and K.C. Wong Education Foundation.

Glossary

Antisilencing function 1 a (ASF1a)
gene encoding a member of the H3/H4 family of histone chaperone proteins; is similar to the antisilencing function-1 gene in yeast. The protein is a key component of a histone donor complex that functions in nucleosome assembly. It interacts with histones H3 and H4 and functions together with a chromatin assembly factor during DNA replication and repair.
Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq)
useful method to map

References (89)

  • G. Rigillo

    LPS-induced histone H3 phospho(Ser10)-acetylation(Lys14) regulates neuronal and microglial neuroinflammatory response

    Brain Behav. Immun.

    (2018)
  • M. Tan

    Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification

    Cell

    (2011)
  • Y. Liu

    Chromodomain Y-like protein-mediated histone crotonylation regulates stress-induced depressive behaviors

    Biol. Psychiatry

    (2019)
  • P. Yu

    Flexible roles for proteoglycan sulfation and receptor signaling

    Trends Neurosci.

    (2018)
  • T. Nakagawa

    The autism-related protein SETD5 controls neural cell proliferation through epigenetic regulation of rDNA expression

    iScience

    (2020)
  • C. Bouchard

    Genomic location of PRMT6-dependent H3R2 methylation is linked to the transcriptional outcome of associated genes

    Cell Rep.

    (2018)
  • M. Tsuboi

    Diverse gene regulatory mechanisms mediated by Polycomb group proteins during neural development

    Curr. Opin. Neurobiol.

    (2019)
  • T. Kondo

    Polycomb potentiates meis2 activation in midbrain by mediating interaction of the promoter with a tissue-specific enhancer

    Dev. Cell

    (2014)
  • J. Kennedy

    KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants

    Genet Med.

    (2019)
  • L.R. Jensen

    Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation

    Am. J. Hum. Genet.

    (2005)
  • R. Qin

    CDYL Deficiency disrupts neuronal migration and increases susceptibility to epilepsy

    Cell Rep.

    (2017)
  • S. Zhao

    Identification and characterization of 'readers' for novel histone modifications

    Curr. Opin. Chem. Biol.

    (2019)
  • E.M. Hildebrand et al.

    Mechanisms and functions of chromosome compartmentalization

    Trends Biochem. Sci.

    (2020)
  • C. Dulac

    Brain function and chromatin plasticity

    Nature

    (2010)
  • T. Shen

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

    Nucleic Acids Res.

    (2018)
  • W. Xia et al.

    Histone variant H3.3 orchestrates neural stem cell differentiation in the developing brain

    Cell Death Differ.

    (2017)
  • C.M. Hammond

    Histone chaperone networks shaping chromatin function

    Nat. Rev. Mol. Cell Biol.

    (2017)
  • B. Bonev

    Multiscale 3D genome rewiring during mouse neural development

    Cell

    (2017)
  • S.J. Elsaesser et al.

    HIRA and Daxx constitute two independent histone H3.3-containing predeposition complexes

    Cold Spring Harb. Symp. Quant. Biol.

    (2010)
  • B. Biterge et al.

    Histone variants: key players of chromatin

    Cell Tissue Res.

    (2014)
  • C. Bonisch et al.

    Histone H2A variants in nucleosomes and chromatin: more or less stable?

    Nucleic Acids Res.

    (2012)
  • C. Zhou

    Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

    Cell Res.

    (2016)
  • V.K. Rao

    Phosphorylation of Tet3 by cdk5 is critical for robust activation of BRN2 during neuronal differentiation

    Nucleic Acids Res.

    (2020)
  • K. Narkaj

    Blocking H2A.Z incorporation via Tip60 inhibition promotes systems consolidation of fear memory in mice

    eNeuro

    (2018)
  • S. Libu

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

    Nucleic Acids Res.

    (2018)
  • Z. Li

    Neural progenitor cells mediated by H2A.Z.2 regulate microglial development via Cxcl14 in the embryonic brain

    Proc. Natl. Acad. Sci. U. S. A.

    (2019)
  • S.M. Wiedemann

    Identification and characterization of two novel primate-specific histone H3 variants, H3.X and H3.Y

    J. Cell Biol.

    (2010)
  • J. Ninkovic

    Gsk3beta/PKA and Gli1 regulate the maintenance of neural progenitors at the midbrain-hindbrain boundary in concert with E(Spl) factor activity

    Development

    (2008)
  • C. Xiong

    UBN1/2 of HIRA complex is responsible for recognition and deposition of H3.3 at cis-regulatory elements of genes in mouse ES cells

    BMC Biol.

    (2018)
  • H.T. Fang

    Global H3.3 dynamic deposition defines its bimodal role in cell fate transition

    Nat. Commun.

    (2018)
  • B.E. Bernstein

    Methylation of histone H3 Lys 4 in coding regions of active genes

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • L. Li

    The COMPASS family protein ASH2L mediates corticogenesis via transcriptional regulation of Wnt signaling

    Cell Reports

    (2019)
  • M.M. Pradeepa

    Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing

    PLoS Genet.

    (2012)
  • J. Shin

    Decoding neural transcriptomes and epigenomes via high-throughput sequencing

    Nat. Neurosci.

    (2014)
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