Epigenomic analysis reveals DNA motifs regulating histone modifications in human and mouse
Epigenomic analysis reveals DNA motifs regulating histone modifications in human and mouse
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DOI：
10.1073/pnas.1813565116
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发表时间：
2019-02-26
影响因子：
11.1
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Ngo, Vu;Chen, Zhao;Wang, Wei
组蛋白被以基因座、细胞类型和发育阶段特异性方式起作用的酶修饰。酶向染色质的募集在多个水平上受到调节，包括与序列特异性DNA结合因子的相互作用。然而，编排特定组蛋白修饰的调节因子的DNA结合特异性尚未被广泛绘制。我们分析了来自NIH Roadmap表观基因组学项目的121种人类细胞类型和组织中的6种组蛋白标记（H3K4me1，H3K4me3，H3K27ac，H3K27me3，K3H9me3，H3K36me3）以及来自小鼠ENCODE Consortium的8种组蛋白标记（添加H3K4me2和H3K9ac）。我们已经在人类和小鼠中分别确定了361和369个DNA基序，它们是每个组蛋白标记的最佳预测。有趣的是，107个人类基序在两个物种之间是保守的。在人胚胎细胞系H1中，我们只突变了特定位点的DNA基序，H3K27ac水平的显著降低验证了扰动基序的调节作用。这些基序的功能也得到了以下证据的支持：组蛋白相关基序，特别是H3K4me3基序，与癌症患者中的数量性状基因座SNP的表达相比，与已知的随机基序相比，与数量性状基因座SNP的表达显著重叠。此外，我们观察到可能的反馈，以控制染色质动力学的发现图案出现在启动子或增强子与各种组蛋白修饰酶。这些结果为揭示表观遗传事件的分子机制铺平了道路，如组蛋白修饰动力学和表观遗传启动。
Histones are modified by enzymes that act in a locus, cell-type, and developmental stage-specific manner. The recruitment of enzymes to chromatin is regulated at multiple levels, including interaction with sequence-specific DNA-binding factors. However, the DNAbinding specificity of the regulatory factors that orchestrate specific histone modifications has not been broadly mapped. We have analyzed 6 histone marks (H3K4me1, H3K4me3, H3K27ac, H3K27me3, K3H9me3, H3K36me3) across 121 human cell types and tissues from the NIH Roadmap Epigenomics Project as well as 8 histone marks (with addition of H3K4me2 and H3K9ac) from the mouse ENCODE Consortium. We have identified 361 and 369 DNA motifs in human and mouse, respectively, that are the most predictive of each histone mark. Interestingly, 107 human motifs are conserved between the two species. In human embryonic cell line H1, we mutated only the found DNA motifs at particular loci and the significant reduction of H3K27ac levels validated the regulatory roles of the perturbed motifs. The functionality of these motifs was also supported by the evidence that histone-associated motifs, especially H3K4me3 motifs, significantly overlap with the expression of quantitative trait loci SNPs in cancer patients more than the known and random motifs. Furthermore, we observed possible feedbacks to control chromatin dynamics as the found motifs appear in the promoters or enhancers associated with various histone modification enzymes. These results pave the way toward revealing the molecular mechanisms of epigenetic events, such as histone modification dynamics and epigenetic priming.