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

101 Citations (Scopus)

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)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number16
DOIs
StatePublished - Apr 17 2012

Fingerprint

Transcriptional Silencer Elements
Epigenomics
Transcription Factors
Ischemia
Methyl-CpG-Binding Protein 2
Stroke
Genes
Histone Deacetylases
AMPA Receptors
Gene Silencing
Transferases
RNA Interference
Histones
Heart Diseases
Hippocampus

Keywords

  • CA1
  • Chromatin remodeling
  • Global ischemia
  • Synaptic plasticity

ASJC Scopus subject areas

  • General

Cite this

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. / Noh, Kyung Min; Hwang, Jee Yeon; Follenzi, Antonia; Athanasiadou, Rodoniki; Miyawaki, Takahiro; Greally, John M.; Bennett, Michael V. L.; Zukin, R. Suzanne.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 16, 17.04.2012.

Research output: Contribution to journalArticle

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