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Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):E3027-36. doi: 10.1073/pnas.1311323110. Epub 2013 Jul 19.

Targeting H3K4 trimethylation in Huntington disease.

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1
Department of Psychiatry and Human Behavior and UCI Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.

Abstract

Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD.

KEYWORDS:

neurodegeneration; polyglutamine

PMID:
23872847
PMCID:
PMC3740882
DOI:
10.1073/pnas.1311323110
[Indexed for MEDLINE]
Free PMC Article

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