title: 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.
authors.affiliation: Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Noh
authors.forename: Jee-Yeon
authors.initials: JY
authors.lastname: Hwang
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.forename: Rodoniki
authors.initials: R
authors.lastname: Athanasiadou
authors.forename: Takahiro
authors.initials: T
authors.lastname: Miyawaki
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.forename: Michael V L
authors.initials: MV
authors.lastname: Bennett
authors.forename: R Suzanne
authors.initials: RS
authors.lastname: Zukin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D002478:Cells, Cultured; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000150:complications; D008297:Male; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D056970:Co-Repressor Proteins; D049452:Green Fluorescent Proteins; D018091:Receptors, AMPA; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C104722:glutamate receptor ionotropic, AMPA 2