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

doi:10.1073/pnas.1311323110

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

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

143 Scopus citations

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 language	English (US)
Pages (from-to)	E3027-E3036
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	110
Issue number	32
DOIs	https://doi.org/10.1073/pnas.1311323110
State	Published - Aug 6 2013

Keywords

Neurodegeneration
Polyglutamine

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1311323110

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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

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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.",

keywords = "Neurodegeneration, Polyglutamine",

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

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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, pp. E3027-E3036. https://doi.org/10.1073/pnas.1311323110

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AU - Vashishtha, Malini

AU - Ng, Christopher W.

AU - Yildirim, Ferah

AU - Gipson, Theresa A.

AU - Kratter, Ian H.

AU - Bodai, Laszlo

AU - Song, Wan

AU - Lau, Alice

AU - Labadorf, Adam

AU - Vogel-Ciernia, Annie

AU - Troncosco, Juan

AU - Ross, Christopher A.

AU - Bates, Gillian P.

AU - Krainc, Dimitri

AU - Sadri-Vakili, Ghazaleh

AU - Finkbeiner, Steven

AU - Lawrence Marsh, J.

AU - Housman, David E.

AU - Fraenkel, Ernest

AU - Thompson, Leslie M.

PY - 2013/8/6

Y1 - 2013/8/6

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AB - 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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Targeting H3K4 trimethylation in Huntington disease

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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