Overexpression of the MYC transcription factor causes its widespread interaction with regulatory elements in the genome but leads to the up- and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time-course analysis of transcription and mRNA dynamics following MYC activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing, and mathematical modeling. Transcriptional activation correlated with the highest increases in MYC binding at promoters. Repression followed a reciprocal scenario, with the lowest gains in MYC binding. Altogether, the relative abundance (henceforth, “share”) of MYC at promoters was the strongest predictor of transcriptional responses in diverse cell types, predominating over MYC's association with the corepressor ZBTB17 (also known as MIZ1). MYC activation elicited immediate loading of RNA polymerase II (RNAPII) at activated promoters, followed by increases in pause-release, while repressed promoters showed opposite effects. Gains and losses in RNAPII loading were proportional to the changes in the MYC share, suggesting that repression by MYC may be partly indirect, owing to competition for limiting amounts of RNAPII. Secondary to the changes in RNAPII loading, the dynamics of elongation and pre-mRNA processing were also rapidly altered at MYC regulated genes, leading to the transient accumulation of partially or aberrantly processed mRNAs. Altogether, our results shed light on how overexpressed MYC alters the various phases of the RNAPII cycle and the resulting transcriptional response.

MYC转录因子的过表达导致其与基因组中调控元件的广泛相互作用，但导致离散基因集的上调和下调。这些选择性转录反应的分子决定因素仍然难以捉摸。在这里，我们基于染色质免疫沉淀，新合成的RNA的代谢标记，广泛的测序和数学建模，提出了在增殖的小鼠成纤维细胞中MYC激活后转录和mRNA动力学的综合时程分析。转录激活与启动子上MYC结合的最高增加相关。压制是在互惠的情况下进行的，MYC绑定的收益最低。总而言之，相对丰度（此后，MYC在启动子上的“份额”是各种细胞类型中转录反应的最强预测因子，超过了MYC与共加压因子ZBTB17（也称为MIZ1）的联系。MYC激活会在激活的启动子上立即加载RNA聚合酶II（RNAPII），然后增加暂停释放，而被抑制的启动子则显示相反的作用。RNAPII负载的得失与MYC份额的变化成正比，这表明由于竞争限制RNAPII的数量，MYC的抑制作用可能是部分间接的。继RNAPII负载的变化之后，MYC调控基因的伸长和前mRNA处理的动力学也迅速改变，从而导致部分或异常处理过的mRNA的瞬时积累。共，