http://www.pnas.org/content/early/2012/02/24/1121568109.short
- Contributed by Michael V. L. Bennett, January 15, 2012 (sent for review December 22, 2011)
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.
Footnotes
- ↵1K.-M.N. and J.-Y.H. contributed equally to this work.
- ↵2To whom correspondence may be addressed. E-mail: michael.bennett@einstein.yu.edu or suzanne.zukin@einstein.yu.edu.
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