Targeting H3K4 trimethylation in Huntington disease

Malini Vashishtha, Christopher W. Ng, Ferah Yildirim, Theresa A. Gipson, Ian H. Kratter, L. 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

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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
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number32
DOIs
Publication statusPublished - Aug 6 2013

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Huntington Disease
Neurons
Epigenomics
Histones
Genes
Lysine
Drosophila
Chromatin
Down-Regulation
Genome
Brain

Keywords

  • Neurodegeneration
  • Polyglutamine

ASJC Scopus subject areas

  • General

Cite this

Targeting H3K4 trimethylation in Huntington disease. / Vashishtha, Malini; Ng, Christopher W.; Yildirim, Ferah; Gipson, Theresa A.; Kratter, Ian H.; Bodai, L.; Song, Wan; Lau, Alice; Labadorf, Adam; Vogel-Ciernia, Annie; Troncosco, Juan; Ross, Christopher A.; Bates, Gillian P.; Krainc, Dimitri; Sadri-Vakili, Ghazaleh; Finkbeiner, Steven; Lawrence Marsh, J.; Housman, David E.; Fraenkel, Ernest; Thompson, Leslie M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 32, 06.08.2013.

Research output: Contribution to journalArticle

Vashishtha, M, Ng, CW, Yildirim, F, Gipson, TA, Kratter, IH, Bodai, L, Song, W, Lau, A, Labadorf, A, Vogel-Ciernia, A, Troncosco, J, Ross, CA, Bates, GP, Krainc, D, Sadri-Vakili, G, Finkbeiner, S, Lawrence Marsh, J, Housman, DE, Fraenkel, E & Thompson, LM 2013, 'Targeting H3K4 trimethylation in Huntington disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 32. https://doi.org/10.1073/pnas.1311323110
Vashishtha, Malini ; Ng, Christopher W. ; Yildirim, Ferah ; Gipson, Theresa A. ; Kratter, Ian H. ; Bodai, L. ; Song, Wan ; Lau, Alice ; Labadorf, Adam ; Vogel-Ciernia, Annie ; Troncosco, Juan ; Ross, Christopher A. ; Bates, Gillian P. ; Krainc, Dimitri ; Sadri-Vakili, Ghazaleh ; Finkbeiner, Steven ; Lawrence Marsh, J. ; Housman, David E. ; Fraenkel, Ernest ; Thompson, Leslie M. / Targeting H3K4 trimethylation in Huntington disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 32.
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