PDF(Pubmed)
Abstract：
RNA polymerase III (Pol III) subunit RPC7α, which is encoded by POLR3G in humans, has been linked to both tumor growth and metastasis. Accordantly, high POLR3G expression is a negative prognostic factor in multiple cancer subtypes. To date, the mechanisms underlying POLR3G upregulation have remained poorly defined. We performed a large-scale genomic survey of mRNA and chromatin signatures to predict drivers of POLR3G expression in cancer. Our survey uncovers positive determinants of POLR3G expression, including a gene-internal super-enhancer bound with multiple transcription factors (TFs) that promote POLR3G expression, as well as negative determinants that include gene-internal DNA methylation, retinoic-acid induced differentiation, and MXD4-mediated disruption of POLR3G expression. We show that novel TFs identified in our survey, including ZNF131 and ZNF207, functionally enhance POLR3G expression, whereas MXD4 likely obstructs MYC-driven expression of POLR3G and other growth-related genes. Integration of chromatin architecture and gene regulatory signatures identifies additional factors, including histone demethylase KDM5B, as likely influencers of POLR3G gene activity. Taken together, our findings support a model in which POLR3G expression is determined with multiple factors and dynamic regulatory programs, expanding our understanding of the circuitry underlying POLR3G upregulation and downstream consequences in cancer.
摘要：
RNA聚合酶III（PolIII）亚基RPC7α，由POLR3G在人类中编码，与肿瘤生长和转移有关.据此，POLR3G高表达是多种癌症亚型的负预后因素。迄今为止,POLR3G上调的潜在机制仍然不明确。我们对mRNA和染色质特征进行了大规模基因组调查，以预测癌症中POLR3G表达的驱动因素。我们的调查揭示了POLR3G表达的积极决定因素，包括与促进POLR3G表达的多个转录因子（TF）结合的基因内部超增强子，以及包括基因内部DNA甲基化在内的负面决定因素，视黄酸诱导分化，和MXD4介导的POLR3G表达的破坏。我们表明，在我们的调查中发现了新的TFs，包括ZNF131和ZNF207，在功能上增强POLR3G表达，而MXD4可能阻碍MYC驱动的POLR3G和其他生长相关基因的表达。染色质结构和基因调控特征的整合确定了其他因素，包括组蛋白去甲基酶KDM5B，可能是POLR3G基因活性的影响者。一起来看,我们的发现支持了一个模型，其中POLR3G表达由多个因素和动态调控程序决定，扩大我们对POLR3G上调和癌症下游后果的潜在电路的理解。
