Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 32, Pages E3027-E3036Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1311323110
Keywords
polyglutamine; neurodegeneration
Categories
Funding
- University of California at San Francisco Medical Scientist Training Program
- National Institute of Health [2R01 NS45491, NS-45283, NS-52789, U01-NS063953, U54-CA112967, R01-GM089903, c NS072793, PN2EY016525]
- National Research Service Award [1F31 NS077543]
- CHDI Foundation
- Huntington's Disease Society of America
- Hereditary Disease Foundation
- Hereditary Disease Foundation through the Leslie Gehry Brenner Award for Innovation in Science
- Koch Institute Support (Core) from the National Cancer Institute [P30-CA14051]
- National Science Foundation [DB1-0821391]
- National Institutes of Health [P30-ES002109]
- Optical Biology Shared Resource of Cancer Center at the University of California at Irvine [CA-62203]
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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.
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