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

Kyung Min Noh, Jee Yeon Hwang, Antonia Follenzi, Rodoniki Athanasiadou, Takahiro Miyawaki, John M. Greally, Michael V.L. Bennett, R. Suzanne Zukin

Research output: Contribution to journalArticle

107 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E962-E971
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number16
DOIs
StatePublished - Apr 17 2012

Keywords

  • CA1
  • Chromatin remodeling
  • Global ischemia
  • Synaptic plasticity

ASJC Scopus subject areas

  • General

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