RNA polymerase III (Pol III) subunit RPC7α, which is encoded byPOLR3Gin humans, has been linked to both tumor growth and metastasis. Accordantly, highPOLR3Gexpression is a negative prognostic factor in multiple cancer subtypes. To date, the mechanisms underlyingPOLR3Gupregulation have remained poorly defined. We performed a large-scale genomic survey of mRNA and chromatin signatures to predict drivers ofPOLR3Gexpression in cancer. Our survey uncovers positive determinants ofPOLR3Gexpression, including a gene-internal super-enhancer bound with multiple transcription factors (TFs) that promotePOLR3Gexpression, as well as negative determinants that include gene-internal DNA methylation, retinoic-acid induced differentiation, and MXD4-mediated disruption ofPOLR3Gexpression. We show that novel TFs identified in our survey, including ZNF131 and ZNF207, functionally enhancePOLR3Gexpression, whereas MXD4 likely obstructs MYC-driven expression ofPOLR3Gand other growth-related genes. Integration of chromatin architecture and gene regulatory signatures identifies additional factors, including histone demethylase KDM5B, as likely influencers ofPOLR3Ggene activity. Taken together, our findings support a model in whichPOLR3Gexpression is determined with multiple factors and dynamic regulatory programs, expanding our understanding of the circuitry underlyingPOLR3Gupregulation and downstream consequences in cancer.
RNA聚合酶III（Pol III）亚基RPC7α由人类基因POLR3G编码，已被证实与肿瘤生长及转移密切相关。相应地，POLR3G的高表达是多种癌症亚型的不良预后因素。迄今为止，POLR3G上调的分子机制尚未明确。我们通过大规模基因组学分析，结合mRNA与染色质特征数据，预测了癌症中驱动POLR3G表达的关键因素。研究发现，POLR3G表达的正向调控因素包括一个位于基因内部的超级增强子，该增强子可与多种转录因子结合并促进POLR3G表达；而负向调控因素则包括基因内部的DNA甲基化、视黄酸诱导的分化过程以及MXD4介导的POLR3G表达抑制。我们证实了研究中新发现的转录因子（如ZNF131和ZNF207）在功能上可增强POLR3G表达，而MXD4则可能阻碍MYC驱动的POLR3G及其他生长相关基因的表达。通过整合染色质结构与基因调控特征，研究还识别出其他潜在调控因子，如组蛋白去甲基化酶KDM5B，可能影响POLR3G基因活性。综上所述，我们的研究支持一个多因素动态调控模型，表明POLR3G的表达受多种因子和动态调控程序共同决定，从而拓展了对POLR3G上调机制及其在癌症中下游效应的调控网络的理解。
肿瘤(癌症)患者之家