Journal Article

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

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

2012

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors / Animals / binding proteins / Biological Sciences / Blotting, Western / Brain / CA1 Region, Hippocampal / CA1 Region, Hippocampal - metabolism / CA1 Region, Hippocampal - pathology / Cancer / Capsaicin receptors / Cardiovascular diseases / Cell Death / Cells, Cultured / Co-Repressor Proteins / Co-Repressor Proteins - genetics / Co-Repressor Proteins - metabolism / Cognitive ability / complications / death / diabetes / Diabetes mellitus / Epigenesis, Genetic / Epigenesis, Genetic - genetics / Epigenetics / Epigenomics / etiology / gene expression / Gene Expression Regulation / Gene silencing / Genes / genetics / Green Fluorescent Proteins / Green Fluorescent Proteins - genetics / Green Fluorescent Proteins - metabolism / heart / Heart diseases / Hippocampus / Histone deacetylase / histones / Humans / Injuries / Ischemia / Ischemia - complications / Male / MeCP2 protein / messenger RNA / metabolism / Microscopy, Fluorescence / Neurodegeneration / neurons / Neurons - metabolism / Neurons - pathology / pathology / PNAS Plus / Promoter Regions, Genetic / Promoter Regions, Genetic - genetics / Promoters / Protein Binding / Proteins / Rats / Rats, Sprague-Dawley / Receptors, AMPA / Receptors, AMPA - genetics / Receptors, AMPA - metabolism / Repressor Proteins / Repressor Proteins - genetics / Repressor Proteins - metabolism / Repressors / Reverse Transcriptase Polymerase Chain Reaction / RNA Interference / Stroke / Stroke - etiology / Stroke - genetics / Stroke - metabolism / transcription (genetics) / Transcription factors