TY - JOUR TI - CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer AU - Ahmed, Musaddeque AU - Soares, Fraser AU - Xia, Ji-Han AU - Yang, Yue AU - Li, Jing AU - Guo, Haiyang AU - Su, Peiran AU - Tian, Yijun AU - Lee, Hyung Joo AU - Wang, Miranda AU - Akhtar, Nayeema AU - Houlahan, Kathleen E. AU - Bosch, Almudena AU - Zhou, Stanley AU - Mazrooei, Parisa AU - Hua, Junjie T. AU - Chen, Sujun AU - Petricca, Jessica AU - Zeng, Yong AU - Davies, Alastair AU - Fraser, Michael AU - Quigley, David A. AU - Feng, Felix Y. AU - Boutros, Paul C. AU - Lupien, Mathieu AU - Zoubeidi, Amina AU - Wang, Liang AU - Walsh, Martin J. AU - Wang, Ting AU - Ren, Shancheng AU - Wei, Gong-Hong AU - He, Housheng Hansen T2 - Nature Communications AB - 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. DA - 2021/03/19/ PY - 2021 DO - 10.1038/s41467-021-21867-0 DP - www.nature.com VL - 12 IS - 1 SP - 1781 LA - en SN - 2041-1723 UR - https://www.nature.com/articles/s41467-021-21867-0 Y2 - 2021/03/19/16:44:10 ER -