Combinatorial binding in human and mouse embryonic stem cells identifies conserved enhancers active in early embryonic development.
Combinatorial binding in human and mouse embryonic stem cells identifies conserved enhancers active in early embryonic development.
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人和小鼠胚胎干细胞中的联合结合鉴定了早期胚胎发育中活跃的保守增强子。
DOI：
10.1371/journal.pcbi.1002304
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发表时间：
2011-12
影响因子：
4.3
通讯作者：
Vingron M
中科院分区：
文献类型：
--
作者：
Göke J;Jung M;Behrens S;Chavez L;O'Keeffe S;Timmermann B;Lehrach H;Adjaye J;Vingron M
转录因子是通过与顺式调节序列如启动子和增强子结合来调节基因表达的蛋白质。在胚胎干（ES）细胞中，转录因子OCT 4、SOX 2和NANOG的结合对于维持细胞分化成发育中胚胎的任何细胞类型的能力是必不可少的。已知转录因子相互作用以调节基因表达。在这项研究中，我们表明，组合结合是强烈相关的共定位的转录辅激活介体，H3K27ac和附近的基因在胚胎干细胞中的表达增加。我们观察到，在胚胎干细胞中，Oct4、Nanog和Sox 2结合的相同位点经常在早期胚胎发育中驱动表达。小鼠和人ES细胞的比较显示，物种之间共享不到5%的OCT 4、SOX 2和NANOG的个体结合事件。相比之下，约15%的组合结合事件，甚至53%至63%的组合结合事件在早期发育中的增强子活性是保守的。我们的分析表明，OCT4，SOX 2和NANOG结合的组合对于ES细胞中的转录至关重要，并且可能通过结合保守的早期发育增强子而对胚胎发生起重要作用。我们的数据表明，调控网络的快速进化重新布线主要影响个体的结合事件，而“基因调控热点”是由多种因素结合，并在整个早期发育的多个组织中活跃，受到更强的进化约束。哺乳动物的身体由数百种不同的细胞类型组成。在胚胎发生过程中，这种多样性是由多个细胞命运决定和分化事件产生的。胚胎干细胞是研究胚胎分化和早期发育的体外模型。它们的多能状态由转录因子如OCT 4、SOX 2和NANOG维持，这些转录因子与基因组内的调控元件结合。理解转录因子结合、基因表达和细胞分化之间的相互作用是理解哺乳动物胚胎发育的关键。在这项研究中，我们发现在ES细胞中OCT 4，SOX 2和NANOG的组合结合鉴定了与活性转录相关的增强子。我们观察到，这些增强子也经常在后期发育阶段表现出活性。使用来自小鼠和人ES细胞的数据，我们发现这些在多能细胞和发育中有活性的组合结合的增强子显示出非常高的结合保守水平（>50%）。我们的分析表明，这些保守的“基因调控热点”整合的转录网络，促进多能性的基因调控网络，促进细胞命运的决定和分化在早期胚胎发育。
Transcription factors are proteins that regulate gene expression by binding to cis-regulatory sequences such as promoters and enhancers. In embryonic stem (ES) cells, binding of the transcription factors OCT4, SOX2 and NANOG is essential to maintain the capacity of the cells to differentiate into any cell type of the developing embryo. It is known that transcription factors interact to regulate gene expression. In this study we show that combinatorial binding is strongly associated with co-localization of the transcriptional co-activator Mediator, H3K27ac and increased expression of nearby genes in embryonic stem cells. We observe that the same loci bound by Oct4, Nanog and Sox2 in ES cells frequently drive expression in early embryonic development. Comparison of mouse and human ES cells shows that less than 5% of individual binding events for OCT4, SOX2 and NANOG are shared between species. In contrast, about 15% of combinatorial binding events and even between 53% and 63% of combinatorial binding events at enhancers active in early development are conserved. Our analysis suggests that the combination of OCT4, SOX2 and NANOG binding is critical for transcription in ES cells and likely plays an important role for embryogenesis by binding at conserved early developmental enhancers. Our data suggests that the fast evolutionary rewiring of regulatory networks mainly affects individual binding events, whereas “gene regulatory hotspots” which are bound by multiple factors and active in multiple tissues throughout early development are under stronger evolutionary constraints. The mammalian body is composed of hundreds of distinct cell types. During embryogenesis, this diversity is created by multiple cell fate decisions and differentiation events. Embryonic stem (ES) cells provide the in vitro model to study differentiation and early development. Their pluripotent state is maintained by transcription factors such as OCT4, SOX2 and NANOG which bind to regulatory elements within the genome. Understanding the interplay between transcription factor binding, gene expression and cellular differentiation is key to understanding the development of the mammalian embryo. In this study we find that combinatorial binding of OCT4, SOX2 and NANOG in ES cells identifies enhancers which are associated with active transcription. We observe that these enhancers also frequently show activity at later developmental stages. Using data from mouse and human ES cells we find that these combinatorially bound enhancers which are active in pluripotent cells and development show extraordinarily high levels of binding conservation (>50%). Our analysis suggests that these conserved “gene regulatory hotspots” integrate the transcriptional network that promotes pluripotency into the gene regulatory networks that promote cell fate decisions and differentiation during early embryonic development.
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影响因子：
30.8
作者：
He, Qiye;Bardet, Anais F.;Zeitlinger, Julia
通讯作者：
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