CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer

Musaddeque Ahmed, Fraser Soares, Ji-Han Xia, Yue Yang, Jing Li, Haiyang Guo, Peiran Su, Yijun Tian, Hyung Joo Lee, Miranda Wang, Nayeema Akhtar, Kathleen E. Houlahan, Almudena Bosch, Stanley Zhou, Parisa Mazrooei, Junjie T. Hua, Sujun Chen, Jessica Petricca, Yong Zeng, Alastair Davies, Michael Fraser, David A. Quigley, Felix Y. Feng, Paul C. Boutros, Mathieu Lupien, Amina Zoubeidi, Liang Wang, Martin J. Walsh, Ting Wang, Shancheng Ren (), Gong-Hong Wei () and Housheng Hansen He ()
Additional contact information
Musaddeque Ahmed: Princess Margaret Cancer Center/University Health Network
Fraser Soares: Princess Margaret Cancer Center/University Health Network
Ji-Han Xia: University of Oulu
Yue Yang: Changhai Hospital
Jing Li: Changhai Hospital
Haiyang Guo: Princess Margaret Cancer Center/University Health Network
Peiran Su: Princess Margaret Cancer Center/University Health Network
Yijun Tian: H. Lee Moffitt Cancer Center and Research Institute
Hyung Joo Lee: Washington University in St. Louis
Miranda Wang: Princess Margaret Cancer Center/University Health Network
Nayeema Akhtar: Princess Margaret Cancer Center/University Health Network
Kathleen E. Houlahan: University of Toronto
Almudena Bosch: Icahn School of Medicine at Mount Sinai
Stanley Zhou: Princess Margaret Cancer Center/University Health Network
Parisa Mazrooei: Princess Margaret Cancer Center/University Health Network
Junjie T. Hua: Princess Margaret Cancer Center/University Health Network
Sujun Chen: Princess Margaret Cancer Center/University Health Network
Jessica Petricca: Princess Margaret Cancer Center/University Health Network
Yong Zeng: Princess Margaret Cancer Center/University Health Network
Alastair Davies: The University of British Columbia
Michael Fraser: Princess Margaret Cancer Center/University Health Network
David A. Quigley: University of California at San Francisco
Felix Y. Feng: University of California at San Francisco
Paul C. Boutros: Vector Institute
Mathieu Lupien: Princess Margaret Cancer Center/University Health Network
Amina Zoubeidi: The University of British Columbia
Liang Wang: H. Lee Moffitt Cancer Center and Research Institute
Martin J. Walsh: Icahn School of Medicine at Mount Sinai
Ting Wang: Washington University in St. Louis
Shancheng Ren: Changhai Hospital
Gong-Hong Wei: University of Oulu
Housheng Hansen He: Princess Margaret Cancer Center/University Health Network

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.

Date: 2021
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DOI: 10.1038/s41467-021-21867-0

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