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

Authors: Noh, Kyung-Min  Hwang, Jee-Yeon  Follenzi, Antonia  Athanasiadou, Rodoniki  Miyawaki, Takahiro  Greally, John M  Bennett, Michael V L  Zukin, R Suzanne 
Citation: Noh KM, etal., Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):E962-71. doi: 10.1073/pnas.1121568109. Epub 2012 Feb 27.
Pubmed: (View Article at PubMed) PMID:22371606
DOI: Full-text: DOI:10.1073/pnas.1121568109

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.

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CRRD Object Information
CRRD ID: 14397566
Created: 2019-04-10
Species: All species
Last Modified: 2019-04-10
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.