Department of Psychiatry and Human Behavior and UCI Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):E3027-36. doi: 10.1073/pnas.1311323110. Epub 2013 Jul 19.
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.
转录失调是亨廷顿病 (HD) 的早期特征。我们在 R6/2 小鼠和人类 HD 大脑中观察到转录抑制启动子处组蛋白 H3 赖氨酸 4 三甲基化 (H3K4me3) 的基因特异性变化。全基因组分析显示了该标记的染色质特征。降低组蛋白 H3K4 去甲基酶 SMCX/Jarid1c 的水平可逆转突变型 Huntingtin 表达引起的关键神经元基因下调。最后,减少 BACHD 小鼠原代神经元中的 SMCX/Jarid1c 或果蝇 HD 模型中的单个 Jarid1 是有保护作用的。因此,靶向该表观遗传特征可能是改善 HD 后果的有效策略。