PDF(Pubmed)
Abstract：
Discontinuous transcription is evolutionarily conserved and a fundamental feature of gene regulation; yet, the exact mechanisms underlying transcriptional bursting are unresolved. Analyses of bursting transcriptome-wide have focused on the role of cis-regulatory elements, but other factors that regulate this process remain elusive. We applied mathematical modeling to single-cell RNA sequencing data to infer bursting dynamics transcriptome-wide under multiple conditions to identify possible molecular mechanisms. We found that Mediator complex subunit 26 (MED26) primarily regulates frequency, MYC regulates burst size, while cohesin and Bromodomain-containing protein 4 (BRD4) can modulate both. Despite comparable effects on RNA levels among these perturbations, acute depletion of MED26 had the most profound impact on the entire gene regulatory network, acting downstream of chromatin spatial architecture and without affecting TATA box-binding protein (TBP) recruitment. These results indicate that later steps in the initiation of transcriptional bursts are primary nodes for integrating gene networks in single cells.
摘要：
不连续转录在进化上是保守的,是基因调控的一个基本特征,转录爆发的确切机制尚未解决。对全转录组爆发的分析集中在顺式调节元件的作用上，但是调节这一过程的其他因素仍然难以捉摸。我们将数学建模应用于单细胞RNA测序数据，以推断在多种条件下全转录组的爆发动力学，以识别可能的分子机制。我们发现介体复合物亚基26（MED26）主要调节频率，MYC调节爆发大小，而粘附蛋白和含溴结构域的蛋白4（BRD4）可以调节两者。尽管这些扰动对RNA水平的影响相当，MED26的急性耗竭对整个基因调控网络产生了最深远的影响，作用于染色质空间结构的下游，不影响TATA盒结合蛋白（TBP）募集。这些结果表明，转录爆发启动的后续步骤是在单细胞中整合基因网络的主要节点。
