Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
Nat Commun. 2021 Mar 19;12(1):1781. doi: 10.1038/s41467-021-21867-0.
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.
前列腺癌（PCa）风险相关 SNP 富集在非编码顺式调控元件（rCREs）中，但它们的作用机制和临床影响仍不清楚。在这里，我们在 PCa 细胞系中进行了 260 个 rCRE 的 CRISPRi 筛选。我们发现，携带高风险 SNP 的 rCREs 对细胞增殖更为重要，并且 H3K27ac 占据是必需性的强指标。我们还表明，细胞系特异性必需 rCREs 在 8q24.21 区域富集，其中包含 rs11986220 的 rCRE 以细胞系特异性方式调节 MYC 和 PVT1 的表达、细胞增殖和肿瘤发生，这取决于该 rCRE 和 MYC 启动子之间的 CTCF 结合位点的 DNA 甲基化协调占据。我们证明，通过 DNA 甲基化水平测量，该位点的 CTCF 沉积在前列腺标本中高度可变，并且在 DNA 甲基化介导的 3D 基因组结构协同驱动下，在 CTCF 结合低的个体中观察到 8q24.21 位点的 MYC eQTL。我们的研究结果强调了一种由风险 SNP 和 DNA 甲基化介导的 3D 基因组结构协同驱动的因果机制，倡导在评估遗传易感性赋予的风险时整合遗传学和表观遗传学。
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