Targeting H3K4 trimethylation in Huntington disease

被引：133

作者：

Vashishtha, Malini ^{[1
,2
]}

Ng, Christopher W.

Yildirim, Ferah

Gipson, Theresa A.

Kratter, Ian H. ^{[5
,6
]}

Bodai, Laszlo ^{[3
,4
]}

Song, Wan ^{[3
,4
]}

Lau, Alice ^{[1
,2
]}

Labadorf, Adam

Vogel-Ciernia, Annie

Troncosco, Juan ^{[9
,10
,11
]}

Ross, Christopher A. ^{[9
,10
,11
]}

Bates, Gillian P. ^{[12
]}

Krainc, Dimitri ^{[13
]}

Sadri-Vakili, Ghazaleh ^{[13
]}

Finkbeiner, Steven ^{[7
,8
]}

Marsh, J. Lawrence ^{[3
,4
]}

Housman, David E.

Fraenkel, Ernest

Thompson, Leslie M. ^{[1
,2
]}

机构：

[1] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92697 USA

[2] Univ Calif Irvine, UCI Inst Memory Impairments & Neurol Disorders, Irvine, CA 92697 USA

[3] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA

[4] Univ Calif Irvine, Ctr Dev Biol, Irvine, CA 92697 USA

[5] Univ Calif San Francisco, Gladstone Inst Neurol Dis, Biomed Sci Grad Program, San Francisco, CA 94158 USA

[6] Univ Calif San Francisco, Med Scientist Training Program, San Francisco, CA 94158 USA

[7] Univ Calif San Francisco, Gladstone Inst Neurol Dis, Taube Koret Ctr Huntingtons Dis Res, Dept Neurol, San Francisco, CA 94158 USA

[8] Univ Calif San Francisco, Gladstone Inst Neurol Dis, Taube Koret Ctr Huntingtons Dis Res, Dept Physiol, San Francisco, CA 94158 USA

[9] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21287 USA

[10] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA

[11] Johns Hopkins Univ, Dept Neurosci & Neuropathol, Baltimore, MD 21287 USA

[12] Kings Coll London, Dept Med & Mol Genet, London SE1 9RT, England

[13] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 32期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

polyglutamine; neurodegeneration; GENE-EXPRESSION; NEUROTROPHIC FACTOR; MUTANT HUNTINGTIN; DNA METHYLATION; TRANSCRIPTIONAL DYSREGULATION; HISTONE METHYLATION; MOUSE MODEL; BDNF; BRAIN; SIGNATURES;

D O I：

10.1073/pnas.1311323110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：E3027 / E3036

页数：10

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