Dynamic chromatin states in human ES cells reveal potential regulatory sequences and genes involved in pluripotency
Dynamic chromatin states in human ES cells reveal potential regulatory sequences and genes involved in pluripotency
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DOI：
10.1038/cr.2011.146
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发表时间：
2011-10-01
期刊：
影响因子：
44.1
通讯作者：
Ren, Bing
中科院分区：
文献类型：
--
作者：
Hawkins, R. David;Hon, Gary C.;Ren, Bing
多能性，细胞分化并产生所有胚胎谱系的能力，定义了少数哺乳动物细胞类型，如胚胎干细胞（ES）。虽然一般认为多能性是激活和维持关键干细胞基因表达的转录调控网络的产物，但越来越多的证据表明表观遗传过程在建立和保护ES细胞的多能性以及维持分化细胞类型的身份方面起着关键作用。为了更好地理解表观遗传机制在多能性中的作用，我们研究了在经历分化成中内胚层谱系的人ES细胞（hESC）中全基因组染色质修饰的动态。我们发现，启动子的染色质修饰在分化过程中基本上保持不变，除了在少数启动子中，H3K27的乙酰化和甲基化之间的动态切换标志着基因表达的激活和沉默之间的过渡，这表明细胞命运承诺在大多数差异表达基因上存在层次结构。我们还绘制了超过50000个潜在的增强子，并观察到染色质修饰的更大动力学，特别是H3K4me1和H3K27ac，它们与其潜在靶基因的表达相关。对这些增强子的进一步分析揭示了多能性的潜在关键转录调节因子和指示可能赋予hESC发育能力的平衡状态的染色质特征。我们的研究结果提供了新的证据，支持染色质修饰在定义增强子和多能性中的作用。
Pluripotency, the ability of a cell to differentiate and give rise to all embryonic lineages, defines a small number of mammalian cell types such as embryonic stem (ES) cells. While it has been generally held that pluripotency is the product of a transcriptional regulatory network that activates and maintains the expression of key stem cell genes, accumulating evidence is pointing to a critical role for epigenetic processes in establishing and safeguarding the pluripotency of ES cells, as well as maintaining the identity of differentiated cell types. In order to better understand the role of epigenetic mechanisms in pluripotency, we have examined the dynamics of chromatin modifications genome-wide in human ES cells (hESCs) undergoing differentiation into a mesendodermal lineage. We found that chromatin modifications at promoters remain largely invariant during differentiation, except at a small number of promoters where a dynamic switch between acetylation and methylation at H3K27 marks the transition between activation and silencing of gene expression, suggesting a hierarchy in cell fate commitment over most differentially expressed genes. We also mapped over 50 000 potential enhancers, and observed much greater dynamics in chromatin modifications, especially H3K4me1 and H3K27ac, which correlate with expression of their potential target genes. Further analysis of these enhancers revealed potentially key transcriptional regulators of pluripotency and a chromatin signature indicative of a poised state that may confer developmental competence in hESCs. Our results provide new evidence supporting the role of chromatin modifications in defining enhancers and pluripotency.