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
收藏
页码：E3027 / E3036
页数：10
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