两篇《细胞》解析干细胞表观遗传学

　　

生物通报道：表观遗传调控，尤其是细胞核内染色体高级组织形式，是目前干细胞研究领域的前沿和热点问题。包括胚胎干细胞和诱导干细胞在内的多能干细胞能利用遗传学和表观遗传学的一种复杂网络，来维持自我更新和多向分化之间的精密平衡。

近期两个研究组分别在Cell杂志上发表文章，报道了人类胚胎干细胞的转录和表观遗传动态机制，以及多向分化胚胎干细胞的表观遗传作用机制。

在第一篇文章：Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells中，来自哈佛麻省Broad研究院，哈佛干细胞研究中心等处的研究人员绘制出了关于人类胚胎干细胞三个胚层中细胞相关转录和表观遗传的全景图。

人类胚胎干细胞（hESCs）分化过程是研究细胞转换调控机制的一个独一无二的模型，因此近年来以胚胎干细胞为模型，研究有关干细胞分化的表观遗传调控已成为新的研究热点。

在这篇文章中，研究人员全面分析了人类胚胎干细胞三个胚层中直接定向分化的细胞，相关转录和表观遗传的特征，绘制出了一副重要的胚胎干细胞转录和表观遗传全景图。

研究人员利用全基因组重亚硫酸盐测序技术，并结合染色质免疫沉淀测序方法，以及RNA测序方法，揭示了与每个胚层细胞系特异性有关的中的特殊事件。在假设远端调控元件中出现了一些显而易见的DNA甲基化和H3K4me1谱系特异性变化，而这些元件均频繁的与未分化人类胚胎干细胞中多能性因子结合在一起。

而且研究人员也在未分化状态的高DNA甲基化位点处，发现了胚层特异性H3K27me3的富集。

深入理解这些初始特异性事件，将有助于找到目前研究方法中的不足之处，从而发现更符合实际的分化策略，以及在细胞转换过程中相关的调控机制。

另外一篇文章中，研究人员全面分析了人类早期发育的基因表达机制，并发现了可能在胚胎遗传和癌症遗传方面发挥重要作用的新的遗传现象。公布的数据包括了超过四年的实验分析，这将极大的帮助生物医学几乎每个子领域的研究工作。

研究人员发现在分析整个基因组的表观遗传组时，调节早期胚胎发育的主控基因往往由组蛋白甲基化H3K27me3关闭。同时，细胞分化的最后阶段主要由DNA甲基化来精心安排，使细胞变得越来越专注于特定的功能。

人类基因组中有超过1200个大型的区域在发育过程中始终没有DNA甲基化的存在。事实证明， 被认为是发育主控因子的许多基因都位于这些区域，研究人员称它们为DNA甲基化谷（DNA methylation valleys， DMVs）。另外，研究人员还发现DMVs在结肠癌细胞中是异常甲基化的。我们知道，异常的DNA甲基化在多种癌症中均发挥重要作用，这些结果暗示，细胞DNA甲基化机制本身的改变可能是肿瘤发展的主要步骤。

这些研究数据将对科学界理解人类早期发展非常有用。这项研究的主要贡献在于为生物医学研究建立了一个主要的信息资源，许多复杂疾病的根源其实早就存在于人类早期发育的过程中了。（生物通：万纹）

原文摘要：

Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells

Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing reveals unique events associated with specification toward each lineage. Lineage-specific dynamic alterations in DNA methylation and H3K4me1 are evident at putative distal regulatory elements that are frequently bound by pluripotency factors in the undifferentiated hESCs. In addition, we identified germ-layer-specific H3K27me3 enrichment at sites exhibiting high DNA methylation in the undifferentiated state. A better understanding of these initial specification events will facilitate identification of deficiencies in current approaches, leading to more faithful differentiation strategies as well as providing insights into the rewiring of human regulatory programs during cellular transitions.

Epigenomic Analysis of Multilineage Differentiation of Human Embryonic Stem Cells

Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in nonexpressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation.