Targeting H3K4 methylation as a therapeutic strategy for Huntington''s disease (ChIP-seq)

Transcriptional dysregulation is an early feature of Huntington''s disease (HD). We observed gene-specific changes in H3K4me3 at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a novel 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 (Htt) 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. Overall design: ChIP-seq for H3K4me3 in wild type and R6/2 cortex and striatum at 8 and 12 weeks.

转录失调是亨廷顿舞蹈症（Huntington's Disease, HD）的早期标志性特征。我们在R6/2小鼠及人类HD患者脑组织的转录抑制型启动子区域，观测到组蛋白H3第4位赖氨酸三甲基化（H3K4me3）存在基因特异性的变化。全基因组分析表明，该修饰存在一种全新的染色质特征。在原代神经元中下调H3K4去甲基化酶SMCX/Jarid1c的表达水平，可逆转由突变型亨廷顿蛋白（mutant Huntingtin, Htt）表达所介导的关键神经元基因下调现象。最终，在BACHD小鼠来源的原代神经元中敲低SMCX/Jarid1c，或是在果蝇HD模型中敲低单个Jarid1基因，均能发挥保护作用。因此，靶向该表观遗传特征或可成为缓解HD病理影响的有效策略。实验整体设计：于8周龄和12周龄时，对野生型与R6/2小鼠的皮层及纹状体组织开展H3K4me3的染色质免疫共沉淀测序（Chromatin Immunoprecipitation sequencing, ChIP-seq）。