Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):E962-71. doi: 10.1073/pnas.1121568109. Epub 2012 Feb 27.

Abstract

Dysregulation of the transcriptional repressor element-1 silencing transcription factor (REST)/neuron-restrictive silencer factor is important in a broad range of diseases, including cancer, diabetes, and heart disease. The role of REST-dependent epigenetic modifications in neurodegeneration is less clear. Here, we show that neuronal insults trigger activation of REST and CoREST in a clinically relevant model of ischemic stroke and that REST binds a subset of "transcriptionally responsive" genes (gria2, grin1, chrnb2, nefh, nfκb2, trpv1, chrm4, and syt6), of which the AMPA receptor subunit GluA2 is a top hit. Genes with enriched REST exhibited decreased mRNA and protein. We further show that REST assembles with CoREST, mSin3A, histone deacetylases 1 and 2, histone methyl-transferase G9a, and methyl CpG binding protein 2 at the promoters of target genes, where it orchestrates epigenetic remodeling and gene silencing. RNAi-mediated depletion of REST or administration of dominant-negative REST delivered directly into the hippocampus in vivo prevents epigenetic modifications, restores gene expression, and rescues hippocampal neurons. These findings document a causal role for REST-dependent epigenetic remodeling in the neurodegeneration associated with ischemic stroke and identify unique therapeutic targets for the amelioration of hippocampal injury and cognitive deficits.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • CA1 Region, Hippocampal / metabolism
  • CA1 Region, Hippocampal / pathology
  • Cell Death
  • Cells, Cultured
  • Co-Repressor Proteins / genetics
  • Co-Repressor Proteins / metabolism
  • Epigenesis, Genetic / genetics*
  • Epigenomics*
  • Gene Expression Regulation
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Ischemia / complications
  • Male
  • Microscopy, Fluorescence
  • Neurons / metabolism*
  • Neurons / pathology
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stroke / etiology
  • Stroke / genetics
  • Stroke / metabolism

Substances

  • Co-Repressor Proteins
  • RE1-silencing transcription factor
  • Receptors, AMPA
  • Repressor Proteins
  • Green Fluorescent Proteins
  • glutamate receptor ionotropic, AMPA 2