Lorenzin Francesca, Benary Uwe, Baluapuri Apoorva, Walz Susanne, Jung Lisa Anna, von Eyss Björn, Kisker Caroline, Wolf Jana, Eilers Martin, Wolf Elmar
Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany.
Group Mathematical Modeling of Cellular Processes, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Elife. 2016 Jul 27;5:e15161. doi: 10.7554/eLife.15161.
Enhanced expression of the MYC transcription factor is observed in the majority of tumors. Two seemingly conflicting models have been proposed for its function: one proposes that MYC enhances expression of all genes, while the other model suggests gene-specific regulation. Here, we have explored the hypothesis that specific gene expression profiles arise since promoters differ in affinity for MYC and high-affinity promoters are fully occupied by physiological levels of MYC. We determined cellular MYC levels and used RNA- and ChIP-sequencing to correlate promoter occupancy with gene expression at different concentrations of MYC. Mathematical modeling showed that binding affinities for interactions of MYC with DNA and with core promoter-bound factors, such as WDR5, are sufficient to explain promoter occupancies observed in vivo. Importantly, promoter affinity stratifies different biological processes that are regulated by MYC, explaining why tumor-specific MYC levels induce specific gene expression programs and alter defined biological properties of cells.
在大多数肿瘤中都观察到MYC转录因子的表达增强。针对其功能提出了两种看似相互矛盾的模型：一种认为MYC增强所有基因的表达，而另一种模型则表明存在基因特异性调控。在此，我们探讨了这样一种假说，即特定的基因表达谱之所以出现，是因为启动子对MYC的亲和力不同，且高亲和力启动子被生理水平的MYC完全占据。我们测定了细胞中的MYC水平，并使用RNA测序和染色质免疫沉淀测序（ChIP-seq）来关联在不同浓度MYC下启动子占据情况与基因表达。数学建模表明MYC与DNA以及与核心启动子结合因子（如WDR5）相互作用的结合亲和力足以解释在体内观察到的启动子占据情况。重要的是，启动子亲和力对受MYC调控的不同生物学过程进行了分层，这解释了为什么肿瘤特异性的MYC水平会诱导特定的基因表达程序并改变细胞的特定生物学特性。
