Neuron-specific chromatin remodeling: a missing link in epigenetic mechanisms underlying synaptic plasticity, memory, and intellectual disability disorders

Neuropharmacology. 2014 May:80:18-27. doi: 10.1016/j.neuropharm.2013.10.002. Epub 2013 Oct 15.

Abstract

Long-term memory formation requires the coordinated regulation of gene expression. Until recently nucleosome remodeling, one of the major epigenetic mechanisms for controlling gene expression, had been largely unexplored in the field of neuroscience. Nucleosome remodeling is carried out by chromatin remodeling complexes (CRCs) that interact with DNA and histones to physically alter chromatin structure and ultimately regulate gene expression. Human exome sequencing and gene wide association studies have linked mutations in CRC subunits to intellectual disability disorders, autism spectrum disorder and schizophrenia. However, how mutations in CRC subunits were related to human cognitive disorders was unknown. There appears to be both developmental and adult specific roles for the neuron specific CRC nBAF (neuronal Brg1/hBrm Associated Factor). nBAF regulates gene expression required for dendritic arborization during development, and in the adult, contributes to long-term potentiation, a form of synaptic plasticity, and long-term memory. We propose that the nBAF complex is a novel epigenetic mechanism for regulating transcription required for long-lasting forms of synaptic plasticity and memory processes and that impaired nBAF function may result in human cognitive disorders.

Keywords: Autism spectrum disorder; Chromatin remodeling; Epigenetics; Intellectual disability disorder; Long-term memory; Long-term potentiation; Nucleosome remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Animals
  • Autistic Disorder / genetics
  • Autistic Disorder / metabolism
  • Autistic Disorder / physiopathology
  • Brain / enzymology
  • Brain / metabolism
  • Chromatin Assembly and Disassembly*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism
  • Cognition Disorders / physiopathology
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Epigenesis, Genetic*
  • Gene Expression Regulation
  • Humans
  • Intellectual Disability / etiology*
  • Memory Disorders / genetics
  • Memory Disorders / metabolism
  • Memory Disorders / physiopathology
  • Memory*
  • Models, Biological*
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuronal Plasticity*
  • Neurons / enzymology
  • Neurons / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nucleosomes / enzymology
  • Nucleosomes / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • ACTL6B protein, human
  • Actins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Nucleosomes
  • SMARCA2 protein, human
  • Transcription Factors
  • SMARCA4 protein, human
  • DNA Helicases