Calcium-dependent dephosphorylation of the histone chaperone DAXX regulates H3.3 loading and transcription upon neuronal activation

Neuron. 2012 Apr 12;74(1):122-35. doi: 10.1016/j.neuron.2012.02.021.

Abstract

Activity-dependent modifications of chromatin are believed to contribute to dramatic changes in neuronal circuitry. The mechanisms underlying these modifications are not fully understood. The histone variant H3.3 is incorporated in a replication-independent manner into different regions of the genome, including gene regulatory elements. It is presently unknown whether H3.3 deposition is involved in neuronal activity-dependent events. Here, we analyze the role of the histone chaperone DAXX in the regulation of H3.3 incorporation at activity-dependent gene loci. DAXX is found to be associated with regulatory regions of selected activity-regulated genes, where it promotes H3.3 loading upon membrane depolarization. DAXX loss not only affects H3.3 deposition but also impairs transcriptional induction of these genes. Calcineurin-mediated dephosphorylation of DAXX is a key molecular switch controlling its function upon neuronal activation. Overall, these findings implicate the H3.3 chaperone DAXX in the regulation of activity-dependent events, thus revealing a new mechanism underlying epigenetic modifications in neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Calcium / metabolism
  • Carrier Proteins / metabolism*
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Epigenesis, Genetic / physiology
  • Gene Expression Regulation / physiology
  • Genes, Immediate-Early
  • Histone Chaperones / metabolism*
  • Histones / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Potentials / physiology*
  • Mice
  • Mice, Knockout
  • Molecular Chaperones
  • Nerve Net / growth & development
  • Nerve Net / metabolism
  • Nerve Net / microbiology
  • Neural Conduction / physiology
  • Neurons / metabolism*
  • Nuclear Proteins / metabolism*
  • Transcription, Genetic / physiology

Substances

  • Carrier Proteins
  • Daxx protein, mouse
  • Histone Chaperones
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Nuclear Proteins
  • Calcineurin
  • Calcium