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研究揭示增强子-启动子的相互作用对转录的非线性控制
2022-04-17 13:14
来源：小柯机器人

近日，瑞士弗雷德里希·米歇尔生物医学研究所Luca Giorgetti及其小组揭示增强子-启动子的相互作用对转录的非线性控制。2022年4月13日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示，哺乳动物的染色体结构被认为是通过调节增强子和启动子之间的三维互动来调节转录，特别是通过CTCF介导的环化和拓扑关联域（TAD）。然而，染色体的相互作用如何实际转化为转录输出仍不清楚。
 
为了解决这个问题，研究人员使用一种检测方法，将一个增强子定位在相对于固定启动子的大量密集染色体位置，并测量启动子的输出和在一个具有最小调节和结构复杂性的基因组区域内的相互作用。对数百个细胞系的定量分析显示，一个增强子的转录效应通过一种非线性关系取决于它与启动子的接触概率。数学建模表明，非线性可能来自于瞬时的增强子-启动子相互作用在单个细胞中转化为较慢的启动子爆发动态，因此将相互作用的时间动态与转录的时间动态脱钩。这就发现了远端增强子如何从大的基因组距离上发挥作用的潜在机制，以及拓扑关联域边界如何阻止远端增强子。最后，结果表明，增强子的强度也决定了绝对转录水平，以及启动子对CTCF介导的转录绝缘的敏感性。这些测量结果为染色体结构在长距离转录调控中的背景依赖作用建立了一般原则。
 
附：英文原文
 
Title: Nonlinear control of transcription through enhancer–promoter interactions

Author: Zuin, Jessica, Roth, Gregory, Zhan, Yinxiu, Cramard, Julie, Redolfi, Josef, Piskadlo, Ewa, Mach, Pia, Kryzhanovska, Mariya, Tihanyi, Gergely, Kohler, Hubertus, Eder, Mathias, Leemans, Christ, van Steensel, Bas, Meister, Peter, Smallwood, Sebastien, Giorgetti, Luca

Issue&Volume: 2022-04-13

Abstract: Chromosome structure in mammals is thought to regulate transcription by modulating three-dimensional interactions between enhancers and promoters, notably through CTCF-mediated loops and topologically associating domains (TADs)1,2,3,4. However, how chromosome interactions are actually translated into transcriptional outputs remains unclear. Here, to address this question, we use an assay to position an enhancer at large numbers of densely spaced chromosomal locations relative to a fixed promoter, and measure promoter output and interactions within a genomic region with minimal regulatory and structural complexity. A quantitative analysis of hundreds of cell lines reveals that the transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a nonlinear relationship. Mathematical modelling suggests that nonlinearity might arise from transient enhancer–promoter interactions being translated into slower promoter bursting dynamics in individual cells, therefore uncoupling the temporal dynamics of interactions from those of transcription. This uncovers a potential mechanism of how distal enhancers act from large genomic distances, and of how topologically associating domain boundaries block distal enhancers. Finally, we show that enhancer strength also determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation. Our measurements establish general principles for the context-dependent role of chromosome structure in long-range transcriptional regulation.

DOI: 10.1038/s41586-022-04570-y

Source: https://www.nature.com/articles/s41586-022-04570-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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