Phase separation and gene control Many components of eukaryotic transcription machinery—such as transcription factors and cofactors including BRD4, subunits of the Mediator complex, and RNA polymerase II—contain intrinsically disordered low-complexity domains. Now a conceptual framework connecting the nature and behavior of their interactions to their functions in transcription regulation is emerging (see the Perspective by Plys and Kingston). Chong et al. found that low-complexity domains of transcription factors form concentrated hubs via functionally relevant dynamic, multivalent, and sequence-specific protein-protein interaction. These hubs have the potential to phase-separate at higher concentrations. Indeed, Sabari et al. showed that at super-enhancers, BRD4 and Mediator form liquid-like condensates that compartmentalize and concentrate the transcription apparatus to maintain expression of key cell-identity genes. Cho et al. further revealed the differential sensitivity of Mediator and RNA polymerase II condensates to selective transcription inhibitors and how their dynamic interactions might initiate transcription elongation. Science, this issue p. eaar2555, p. eaar3958, p. 412; see also p. 329 Critical components of transcription machinery form stable, condensate-like, transcription-dependent clusters in cells. Models of gene control have emerged from genetic and biochemical studies, with limited consideration of the spatial organization and dynamics of key components in living cells. We used live-cell superresolution and light-sheet imaging to study the organization and dynamics of the Mediator coactivator and RNA polymerase II (Pol II) directly. Mediator and Pol II each form small transient and large stable clusters in living embryonic stem cells. Mediator and Pol II are colocalized in the stable clusters, which associate with chromatin, have properties of phase-separated condensates, and are sensitive to transcriptional inhibitors. We suggest that large clusters of Mediator, recruited by transcription factors at large or clustered enhancer elements, interact with large Pol II clusters in transcriptional condensates in vivo.

中文翻译：

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介质和 RNA 聚合酶 II 簇在转录依赖的凝聚物中结合

相分离和基因控制 真核转录机制的许多组成部分——例如转录因子和辅因子，包括 BRD4、介质复合体的亚基和 RNA 聚合酶 II——包含本质上无序的低复杂性域。现在，一个将它们相互作用的性质和行为与其在转录调控中的功能联系起来的概念框架正在出现（参见 Plys 和 Kingston 的观点）。冲等人。发现转录因子的低复杂性域通过功能相关的动态、多价和序列特异性蛋白质-蛋白质相互作用形成集中的枢纽。这些中心有可能在更高的浓度下进行相分离。事实上，Sabari 等人。表明在超级增强器中，BRD4 和 Mediator 形成液体状凝聚物，将转录装置区分开来并集中起来，以维持关键细胞身份基因的表达。Cho 等人。进一步揭示了 Mediator 和 RNA 聚合酶 II 缩合物对选择性转录抑制剂的不同敏感性，以及它们的动态相互作用如何启动转录延伸。科学，这个问题 p。eaar2555, 页。eaar3958，第。第412话 另见第。329 转录机制的关键组成部分在细胞中形成稳定的、类似凝聚物的转录依赖性簇。基因控制模型来自遗传和生化研究，对活细胞关键成分的空间组织和动力学的考虑有限。我们使用活细胞超分辨率和光片成像来直接研究介质共激活剂和 RNA 聚合酶 II (Pol II) 的组织和动力学。Mediator 和 Pol II 各自在活胚胎干细胞中形成小的瞬时和大的稳定簇。Mediator 和 Pol II 共定位在稳定的簇中，与染色质相关联，具有相分离凝聚物的特性，并且对转录抑制剂敏感。我们建议由转录因子在大的或成簇的增强子元件中招募的大簇中介体与体内转录凝聚物中的大 Pol II 簇相互作用。Mediator 和 Pol II 共定位在稳定的簇中，与染色质相关联，具有相分离凝聚物的特性，并且对转录抑制剂敏感。我们建议由转录因子在大的或成簇的增强子元件中招募的大簇介体与体内转录凝聚物中的大 Pol II 簇相互作用。Mediator 和 Pol II 共定位在稳定的簇中，与染色质相关联，具有相分离凝聚物的特性，并且对转录抑制剂敏感。我们建议由转录因子在大的或成簇的增强子元件中招募的大簇介体与体内转录凝聚物中的大 Pol II 簇相互作用。