The Role of H3K4me3 in Transcriptional Regulation Is Altered in Huntington's Disease.
The Role of H3K4me3 in Transcriptional Regulation Is Altered in Huntington's Disease.
复制标题
DOI：
10.1371/journal.pone.0144398
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Weng Z
中科院分区：
文献类型：
--
作者：
Dong X;Tsuji J;Labadorf A;Roussos P;Chen JF;Myers RH;Akbarian S;Weng Z
亨廷顿病（HD）是由亨廷顿蛋白（HTT）基因中CAG重复序列扩增引起的常染色体显性遗传性神经退行性疾病。先前的研究表明，突变HTT可以改变与失调的表观遗传修饰相关的基因表达。研究最广泛的染色质修饰之一是组蛋白3的三甲基化赖氨酸4（H3K4me3）。在这里，我们进行了第一次全面的研究H3K4me3 ChIP测序的神经元染色质从前额叶皮质的六个HD的情况下，六个非神经系统的控制，其与基因表达的RNA测序测量。我们在HD和对照组之间检测到2，830个差异富集的H3K4me3峰，其中55%在HD中下调。尽管H3 K4 me3信号预计与mRNA水平相关，但我们发现改变的H3 K4 me3峰和mRNA水平之间存在意想不到的不一致。具有差异H3K4me3峰的基因的基因本体（GO）术语富集分析揭示了仅在HD中具有下调信号的基因中统计学显著富集的GO术语。最常涉及的生物过程术语是器官形态发生和基因表达的正调控。超过9，000个H3K4me3峰不位于任何识别的转录起始位点附近，并且这些“远端”峰中的约36%共定位于已知的增强子位点。六个转录因子和染色质重塑差异富集在HD H3K4me3远端峰，包括EZH2和SUZ12，多梳抑制复合物2（PRC2）的两个核心亚基。此外，PRC2抑制状态在HD富集峰中显著耗尽，表明PRC2抑制与亨廷顿病中上调的H3 K4 me3相关的表观遗传作用。总之，我们的研究提供了新的见解转录失调的亨廷顿病通过分析分化的H3 K4 me3富集。
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder resulting from expansion of CAG repeats in the Huntingtin (HTT) gene. Previous studies have shown mutant HTT can alter expression of genes associated with dysregulated epigenetic modifications. One of the most widely studied chromatin modifications is trimethylated lysine 4 of histone 3 (H3K4me3). Here, we conducted the first comprehensive study of H3K4me3 ChIP-sequencing in neuronal chromatin from the prefrontal cortex of six HD cases and six non-neurologic controls, and its association with gene expression measured by RNA-sequencing. We detected 2,830 differentially enriched H3K4me3 peaks between HD and controls, with 55% of them down-regulated in HD. Although H3K4me3 signals are expected to be associated with mRNA levels, we found an unexpected discordance between altered H3K4me3 peaks and mRNA levels. Gene ontology (GO) term enrichment analysis of the genes with differential H3K4me3 peaks, revealed statistically significantly enriched GO terms only in the genes with down-regulated signals in HD. The most frequently implicated biological process terms are organ morphogenesis and positive regulation of gene expression. More than 9,000 H3K4me3 peaks were located not near any recognized transcription start sites and approximately 36% of these “distal” peaks co-localized to known enhancer sites. Six transcription factors and chromatin remodelers are differentially enriched in HD H3K4me3 distal peaks, including EZH2 and SUZ12, two core subunits of the polycomb repressive complex 2 (PRC2). Moreover, PRC2 repressive state was significantly depleted in HD-enriched peaks, suggesting the epigenetic role of PRC2 inhibition associated with up-regulated H3K4me3 in Huntington’s disease. In summary, our study provides new insights into transcriptional dysregulation of Huntington’s disease by analyzing the differentiation of H3K4me3 enrichment.