Integrative analysis of RNA polymerase II and transcriptional dynamics upon MYC activation.
Integrative analysis of RNA polymerase II and transcriptional dynamics upon MYC activation.
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DOI：
10.1101/gr.226035.117
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发表时间：
2017-10
期刊：
影响因子：
7
通讯作者：
Pelizzola M
中科院分区：
文献类型：
--
作者：
de Pretis S;Kress TR;Morelli MJ;Sabò A;Locarno C;Verrecchia A;Doni M;Campaner S;Amati B;Pelizzola M
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，但导致离散基因组的上调和下调。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RNA的代谢标记、广泛测序和数学模型，对增殖小鼠成纤维细胞MYC激活后的转录和mRNA动力学进行了综合时间过程分析。转录激活与MYC在启动子上结合的最高增加相关。抑制发生在相互作用的情况下，MYC结合的增益最低。总之，MYC启动子的相对丰度（因此称为“份额”）是不同细胞类型中转录反应的最强预测因子，占主导地位，而不是MYC与辅助抑制因子ZBTB17（也称为MIZ1）的关联。MYC激活引发激活启动子处的RNA聚合酶II （RNAPII）立即加载，随后暂停释放增加，而抑制启动子则表现出相反的效果。RNAPII加载的增益和损失与MYC份额的变化成正比，这表明MYC的抑制可能部分是间接的，因为竞争限制了RNAPII的数量。继RNAPII负载变化之后，MYC调控基因的延伸和前mrna加工动态也迅速改变，导致部分或异常加工mrna的短暂积累。总之，我们的研究结果揭示了MYC过表达如何改变RNAPII周期的各个阶段以及由此产生的转录反应。
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.
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