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

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.
AuthorsKyung-Min Noh, Jee-Yeon Hwang, Antonia Follenzi, Rodoniki Athanasiadou, Takahiro Miyawaki, John M Greally, Michael V L Bennett, R Suzanne Zukin
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 16 Pg. E962-71 (Apr 17 2012) ISSN: 1091-6490 [Electronic] United States
PMID22371606 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Co-Repressor Proteins
  • RE1-silencing transcription factor
  • Receptors, AMPA
  • Repressor Proteins
  • Green Fluorescent Proteins
  • glutamate receptor ionotropic, AMPA 2
Topics
  • Animals
  • Blotting, Western
  • CA1 Region, Hippocampal (metabolism, pathology)
  • Cell Death
  • Cells, Cultured
  • Co-Repressor Proteins (genetics, metabolism)
  • Epigenesis, Genetic (genetics)
  • Epigenomics
  • Gene Expression Regulation
  • Green Fluorescent Proteins (genetics, metabolism)
  • Humans
  • Ischemia (complications)
  • Male
  • Microscopy, Fluorescence
  • Neurons (metabolism, pathology)
  • Promoter Regions, Genetic (genetics)
  • Protein Binding
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA (genetics, metabolism)
  • Repressor Proteins (genetics, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stroke (etiology, genetics, metabolism)

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