H3K4me3 instructs transcription at intergenic active regulatory elements [ATAC-seq]

Tri-methylation of lysine 4 on histone H3 (H3K4me3) is a deeply conserved and functionally important histone modification enriched at transcriptionally active promoters. H3K4me3 can facilitate RNA polymerase activity in a context-dependent manner. Here, we generated an epigenetic editing tool, dCas9-PRDM9, that efficiently deposits H3K4me3 at specific target loci, and used it to interrogate the genomic and chromatin contexts required for H3K4me3 to facilitate transcription in human cells. We found that H3K4me3 deposition is sufficient to increase transcription at active candidate cis-regulatory elements (cCREs), and that this effect was independent of cCRE identity or distance from gene promoters, unrelated to transcript levels of putative target genes, and dependent on the presence of active chromatin features. We conclude that H3K4me3 is sufficient to instruct RNA polymerase activity but requires pre-existing features of transcriptionally active chromatin. These findings suggest that disease-associated dysfunction in H3K4me3 deposition or removal can disrupt the cell’s transcriptional state. ATAC-seq from MDA-MB-231 human breast cancer cells

组蛋白H3赖氨酸4三甲基化（H3K4me3）是一种高度保守且功能关键的组蛋白修饰，富集于转录活跃的启动子区域。H3K4me3可依语境调控RNA聚合酶活性。本研究构建了表观遗传编辑工具dCas9-PRDM9，可高效在特定靶位点沉积H3K4me3，并借此探究人类细胞中H3K4me3促进转录所需的基因组与染色质语境。研究发现，H3K4me3沉积足以提升活跃候选顺式调控元件（candidate cis-regulatory elements，cCREs）处的转录水平，且该效应与cCREs的特性或其距基因启动子的距离无关，亦与推定靶基因的转录本水平无关，仅依赖于活跃染色质特征的存在。综上，H3K4me3足以指导RNA聚合酶活性，但需依赖转录活跃染色质的预存特征。上述研究结果提示，与疾病相关的H3K4me3沉积或去除功能异常，可扰乱细胞的转录状态。本数据集包含来自MDA-MB-231人乳腺癌细胞的转座酶可及性测序（ATAC-seq）数据？不，修正后应为：本数据集包含来自MDA-MB-231人乳腺癌细胞的转座酶可及性测序（ATAC-seq）数据。