Super-enhancers in transcriptional regulation and genome organization
Super-enhancers in transcriptional regulation and genome organization
复制标题
转录调控和基因组组织的超级增强子
DOI：
10.1093/nar/gkz1038
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发表时间：
2019-12-16
影响因子：
14.9
通讯作者：
Yan, Jian
中科院分区：
文献类型：
--
作者：
Wang, Xi;Cairns, Murray J.;Yan, Jian
摘要 基因表达以阶段和细胞类型特异性方式精确控制，主要是通过顺式调节元件及其相关反式作用因子之间的相互作用。当这些组件聚集在启动子和增强子中时，它们能够合作调节染色质结构并支持参与塑造细胞基因组结构动态的远程 3D 上层结构。最近，术语“超级增强子”被引入来描述一个高度活跃的调节域，其中包含一系列复杂的序列元件，这些序列元件一起工作来控制涉及细胞身份的关键基因网络。在这里，我们调查了超级增强子与其他增强子类型相比的独特特征，并总结了我们对其在基因调控中的生物学作用的理解的最新进展。我们特别讨论了它们吸引相分离凝聚物形成的能力，以及生成精确激活其靶基因的三维基因组结构的能力。我们还提出了一个多阶段转变模型来解释驱动复杂生物体中超级增强子发展的进化压力，并强调参与肿瘤发生的潜力。最后，我们更广泛地讨论超级增强剂在人类健康疾病中的作用以及治疗干预中的相关潜力。
Abstract Gene expression is precisely controlled in a stage and cell-type-specific manner, largely through the interaction between cis-regulatory elements and their associated trans-acting factors. Where these components aggregate in promoters and enhancers, they are able to cooperate to modulate chromatin structure and support the engagement in long-range 3D superstructures that shape the dynamics of a cell's genomic architecture. Recently, the term ‘super-enhancer’ has been introduced to describe a hyper-active regulatory domain comprising a complex array of sequence elements that work together to control the key gene networks involved in cell identity. Here, we survey the unique characteristics of super-enhancers compared to other enhancer types and summarize the recent advances in our understanding of their biological role in gene regulation. In particular, we discuss their capacity to attract the formation of phase-separated condensates, and capacity to generate three-dimensional genome structures that precisely activate their target genes. We also propose a multi-stage transition model to explain the evolutionary pressure driving the development of super-enhancers in complex organisms, and highlight the potential for involvement in tumorigenesis. Finally, we discuss more broadly the role of super-enhancers in human health disorders and related potential in therapeutic interventions.