Nonlinear control of transcription through enhancer-promoter interactions.
Nonlinear control of transcription through enhancer-promoter interactions.
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DOI：
10.1038/s41586-022-04570-y
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发表时间：
2022-04
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
哺乳动物的染色体结构被认为通过调节增强子和启动子之间的三维相互作用来调节转录，特别是通过CTCF介导的环和拓扑相关结构域（TADs）。然而，染色体相互作用如何实际转化为转录产物仍不清楚。在这里，为了解决这个问题，我们使用一种测定法将增强子定位在相对于固定启动子的大量密集间隔的染色体位置，并以最小的调控和结构复杂性测量基因组区域内的启动子输出和相互作用。对数百个细胞系的定量分析表明，增强子的转录效应取决于其与启动子的接触概率，这是一种非线性关系。数学建模表明，非线性可能会出现从瞬时增强子-启动子相互作用被翻译成较慢的启动子爆发动力学在个别细胞，因此解耦的时间动力学的相互作用从那些转录。这揭示了一个潜在的机制，远端增强子如何从大的基因组距离，以及如何拓扑关联域边界块远端增强子。最后，我们发现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。我们的测量建立了染色体结构在远程转录调控中的上下文依赖性作用的一般原则。增强子的转录效应取决于其与启动子的接触概率，通过非线性关系，增强子强度决定绝对转录水平以及启动子对CTCF介导的转录隔离的敏感性。
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). 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. The transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a nonlinear relationship, and enhancer strength determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation.
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影响因子：
64.5
作者：
Dekker J;Mirny L
通讯作者：
Mirny L
DOI：
10.1242/dev.108480
发表时间：
2014-10
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Anderson E;Devenney PS;Hill RE;Lettice LA
通讯作者：
Lettice LA
预测聚合物建模揭示了染色体构象和转录中的波动耦合。
影响因子：
64.5
作者：
Giorgetti L;Galupa R;Nora EP;Piolot T;Lam F;Dekker J;Tiana G;Heard E
通讯作者：
Heard E
影响因子：
64.5
作者：
Dowen JM;Fan ZP;Hnisz D;Ren G;Abraham BJ;Zhang LN;Weintraub AS;Schujiers J;Lee TI;Zhao K;Young RA
通讯作者：
Young RA
影响因子：
30.8
作者：
Fulco, Charles P.;Nasser, Joseph;Engreitz, Jesse M.
通讯作者：
Engreitz, Jesse M.