Radboud University Nijmegen, Department of Molecular Developmental Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Nijmegen 6500 HB, The Netherlands.
Genome Res. 2014 Mar;24(3):401-10. doi: 10.1101/gr.159608.113. Epub 2013 Dec 11.
During embryonic development, maintenance of cell identity and lineage commitment requires the Polycomb-group PRC2 complex, which catalyzes histone H3 lysine 27 trimethylation (H3K27me3). However, the developmental origins of this regulation are unknown. Here we show that H3K27me3 enrichment increases from blastula stages onward in embryos of the Western clawed frog (Xenopus tropicalis) within constrained domains strictly defined by sequence. Strikingly, although PRC2 also binds widely to active enhancers, H3K27me3 is only deposited at a small subset of these sites. Using a Support Vector Machine algorithm, these sequences can be predicted accurately on the basis of DNA sequence alone, with a sequence signature conserved between humans, frogs, and fish. These regions correspond to the subset of blastula-stage DNA methylation-free domains that are depleted for activating promoter motifs, and enriched for motifs of developmental factors. These results imply a genetic-default model in which a preexisting absence of DNA methylation is the major determinant of H3K27 methylation when not opposed by transcriptional activation. The sequence and motif signatures reveal the hierarchical and genetically inheritable features of epigenetic cross-talk that impose constraints on Polycomb regulation and guide H3K27 methylation during the exit of pluripotency.
在胚胎发育过程中，维持细胞身份和谱系决定需要 Polycomb 组 PRC2 复合物，该复合物催化组蛋白 H3 赖氨酸 27 三甲基化 (H3K27me3)。然而，这种调控的发育起源尚不清楚。在这里，我们表明在西方爪蟾 (Xenopus tropicalis) 胚胎中，H3K27me3 富集从囊胚阶段开始增加，并且在严格由序列定义的受限域内。引人注目的是，尽管 PRC2 也广泛结合到活性增强子上，但 H3K27me3 仅沉积在这些位点的一小部分。使用支持向量机算法，可以仅根据 DNA 序列准确预测这些序列，人类、青蛙和鱼类之间存在保守的序列特征。这些区域对应于囊胚期 DNA 去甲基化无的亚区，这些区域缺乏激活启动子基序，而富含发育因子的基序。这些结果表明了一种遗传默认模型，其中在没有转录激活的情况下，预先存在的 DNA 甲基化缺失是 H3K27 甲基化的主要决定因素。序列和基序特征揭示了表观遗传串扰的分层和遗传可继承特征，这些特征对 Polycomb 调节施加了限制，并指导多能性退出过程中的 H3K27 甲基化。
