A Combinatorial Regulatory Platform Determines Expression of RNA Polymerase III Subunit RPC7α (POLR3G) in Cancer

Author:

Cheng Ruiying1ORCID,Zhou Sihang1,K C Rajendra2,Lizarazo Simon3,Mouli Leela4,Jayanth Anshita4,Liu Qing56,Van Bortle Kevin147

Affiliation:

1. Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA

2. Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA

3. Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA

4. School of Molecular and Cellular Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA

5. Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA

6. Center for Human Genetics, Clemson University, Greenwood, SC 29646, USA

7. Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA

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.

Funder

National Institutes of Health, National Human Genome Research Institute

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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