Targeting H3K4 trimethylation in Huntington disease

Malini Vashishtha, Christopher W. Ng, Ferah Yildirim, Theresa A. Gipson, Ian H. Kratter, Laszlo Bodai, Wan Song, Alice Lau, Adam Labadorf, Annie Vogel-Ciernia, Juan Troncosco, Christopher A. Ross, Gillian P. Bates, Dimitri Krainc, Ghazaleh Sadri-Vakili, Steven Finkbeiner, J. Lawrence Marsh, David E. Housman, Ernest Fraenkel, Leslie M. Thompson

Research output: Contribution to journalArticle

80 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E3027-E3036
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number32
DOIs
Publication statusPublished - Aug 6 2013

    Fingerprint

Keywords

  • Neurodegeneration
  • Polyglutamine

ASJC Scopus subject areas

  • General

Cite this

Vashishtha, M., Ng, C. W., Yildirim, F., Gipson, T. A., Kratter, I. H., Bodai, L., Song, W., Lau, A., Labadorf, A., Vogel-Ciernia, A., Troncosco, J., Ross, C. A., Bates, G. P., Krainc, D., Sadri-Vakili, G., Finkbeiner, S., Lawrence Marsh, J., Housman, D. E., Fraenkel, E., & Thompson, L. M. (2013). Targeting H3K4 trimethylation in Huntington disease. Proceedings of the National Academy of Sciences of the United States of America, 110(32), E3027-E3036. https://doi.org/10.1073/pnas.1311323110