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[交流] 【分享】特异的染色质签名揭示人类早期发育的增强子已有1人参与

A unique chromatin signature uncovers early developmental enhancers in humans
特异的染色质签名揭示人类早期发育的增强子
Alvaro Rada-Iglesias,1 RuchiBajpai,1 TomekSwigut,1 Samantha A. Brugmann,1 Ryan A. Flynn1 & Joanna Wysocka
Nature Volume: 470, Pages: 279–283 Date published: (10 February 2011) DOI: doi:10.1038/nature09692 Received 04 August 2010 Accepted 25 November 2010 Published online 15 December 2010
摘要：Cell-fate transitions involve the integration of genomic information encoded by regulatory elements, such as enhancers, with thecellular environment1, 2. However, identification of genomic sequences that control human embryonic development represents a formidable challenge3. Here we show that in human embryonic stem cells (hESCs), unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, monomethylationof histoneH3 at lysine 4 (H3K4me1), and low nucleosomaldensity. In addition, elements of the first class are distinguished by the acetylationof histoneH3 at lysine 27 (H3K27ac), overlap with previously characterized hESCenhancers, and are located proximally to genes expressed in hESCsand the epiblast. In contrast, elements of the second class, which we term ‘poised enhancers’, are distinguished by the absence of H3K27ac, enrichment of histoneH3 lysine 27 trimethylation(H3K27me3), and are linked to genes inactive in hESCsand instead are involved in orchestrating early steps in embryogenesis, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCsto neuroepithelium, a neuroectoderm-specific subset of poised enhancers acquires a chromatin signature associated with active enhancers. When assayed in zebrafishembryos, poised enhancers are able to direct cell-type and stage-specific expression characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome.Our data demonstrate that early developmental enhancers are epigenetically pre-marked in hESCsand indicate an unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the wealth of new regulatory sequences identified here provides an invaluable resource for studies and isolation of transient, rare cell populations representing early stages of human embryogenesis.
1.细胞命运的变迁包含调控元件（如增强子）编码的基因组信息与细胞环境的整合。然而，发现调控人类干细胞发育的序列是一个巨大的挑战。这里，我们展示了在人胚胎干细胞（hESC）中，特异的染色质签名鉴别两类不同的不同的基因组元件，两者均有p300和BRG1标记及组蛋白H3 4位赖氨酸的单甲基化（H3K4me1），低的核小体密度。
2.另外，一类元件有组蛋白H3 27位赖氨酸的乙酰化（H3K27ac），与之前报道的hESC增强子重叠，邻近于hESC表达的基因并位于外胚层。相反，第二类，叫做“平衡增强子”，含H3K27ac ，组蛋白H3 27位赖氨酸的三甲基化（H3K27me3），并与hESC中沉默的基因相关及参与早期的胚胎形成，如原肠胚、中胚层和神经胚的形成。当hESC分化为神经上皮时，神经外胚层特异的一组平衡增强子获得有活性增强子的染色质签名。在斑马鱼的胚胎中，平衡增强子能指挥细胞型及时期特异的邻近发育基因的表达，即使是在序列不保守的鱼基因组中也是一样。
3.我们的数据阐释了早期发育的增强子在hESC中是预先有表观遗传学修饰的并说明H3K27me3作为远端调控元件的作用。此外，我们发现的这些新的调控序列为变迁的研究提供了丰富的资源，仅有较少的细胞类群代表了早期的人类胚胎发育。
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