Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3

EMBO Rep. 2015 Apr;16(4):528-38. doi: 10.15252/embr.201439092. Epub 2015 Feb 9.

Abstract

Many causal mutations of intellectual disability have been found in genes involved in epigenetic regulations. Replication-independent deposition of the histone H3.3 variant by the HIRA complex is a prominent nucleosome replacement mechanism affecting gene transcription, especially in postmitotic neurons. However, how HIRA-mediated H3.3 deposition is regulated in these cells remains unclear. Here, we report that dBRWD3, the Drosophila ortholog of the intellectual disability gene BRWD3, regulates gene expression through H3.3, HIRA, and its associated chaperone Yemanuclein (YEM), the fly ortholog of mammalian Ubinuclein1. In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation. Inactivation of yem or H3.3 remarkably suppresses the global transcriptome changes and various developmental defects caused by dBRWD3 mutations. Our work thus establishes a previously unknown negative regulation of H3.3 and advances our understanding of BRWD3-dependent intellectual disability.

Keywords: BRWD3; HIRA; YEM; histone H3.3; intellectual disability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Chromatin / chemistry
  • Chromatin / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism
  • Gene Expression Regulation, Developmental*
  • Histone Chaperones / genetics*
  • Histone Chaperones / metabolism
  • Histones / antagonists & inhibitors
  • Histones / genetics*
  • Histones / metabolism
  • Humans
  • Intellectual Disability / genetics
  • Intellectual Disability / metabolism
  • Intellectual Disability / pathology
  • Morphogenesis / genetics
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • BRWD3 protein, human
  • Cell Cycle Proteins
  • Chromatin
  • DNA-Binding Proteins
  • Drosophila Proteins
  • HIRA protein, human
  • Hira protein, Drosophila
  • Histone Chaperones
  • Histones
  • Nuclear Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • UBN1 protein, human
  • yem protein, Drosophila