Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, United States.
Elife. 2020 Dec 7;9:e59388. doi: 10.7554/eLife.59388.
Two different cell signals often affect transcription of the same gene. In such cases, it is natural to ask how the combined transcriptional response compares to the individual responses. The most commonly used mechanistic models predict additive or multiplicative combined responses, but a systematic genome-wide evaluation of these predictions is not available. Here, we analyzed the transcriptional response of human MCF-7 cells to retinoic acid and TGF-β, applied individually and in combination. The combined transcriptional responses of induced genes exhibited a range of behaviors, but clearly favored both additive and multiplicative outcomes. We performed paired chromatin accessibility measurements and found that increases in accessibility were largely additive. There was some association between super-additivity of accessibility and multiplicative or super-multiplicative combined transcriptional responses, while sub-additivity of accessibility associated with additive transcriptional responses. Our findings suggest that mechanistic models of combined transcriptional regulation must be able to reproduce a range of behaviors.
两种不同的细胞信号通常会影响同一基因的转录。在这种情况下，自然会问组合转录反应如何与单个反应相比。最常用的机制模型预测加性或乘法组合反应，但这些预测的系统全基因组评估尚不可用。在这里，我们分析了人类 MCF-7 细胞对维甲酸和 TGF-β的转录反应，分别和联合应用。诱导基因的组合转录反应表现出一系列行为，但显然有利于加性和乘法结果。我们进行了配对染色质可及性测量，发现可及性增加在很大程度上是加性的。可及性的超加性与乘法或超乘法组合转录反应之间存在一定的关联，而可及性的亚加性与转录反应的加性有关。我们的研究结果表明，组合转录调控的机制模型必须能够再现一系列行为。
