Ahmed, M., Soares, F., Xia, JH. et al. CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer. Nat Commun 12, 1781 (2021). https://doi.org/10.1038/s41467-021-21867-0
CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer
|Author:||Ahmed, Musaddeque1; Soares, Fraser1; Xia, Ji-Han2;|
1Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada.
2Univ Oulu, Fac Biochem & Mol Med, Bioctr Oulu, Oulu, Finland.
3Changhai Hosp, Shanghai, Peoples R China.
4Univ Toronto, Dept Med Biophys, Toronto, ON, Canada.
5H Lee Moffitt Canc Ctr & Res Inst, Dept Tumor Biol, Tampa, FL USA.
6Washington Univ, Dept Genet, St Louis, MO 63110 USA.
7Ontario Inst Canc Res, Toronto, ON, Canada.
8Vector Inst, Toronto, ON, Canada.
9Univ Calif Los Angeles, Dept Urol, David Geffen Sch Med, Los Angeles, CA USA.
10Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY USA.
11Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY USA.
12Univ British Columbia, Vancouver Prostate Ctr, Vancouver Gen Hosp, Vancouver, BC, Canada.
13Univ British Columbia, Dept Urol Sci, Vancouver, BC, Canada.
14Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA.
15Univ Calif San Francisco, Dept Urol, San Francisco, CA USA.
16Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
17Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA USA.
18Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA.
19Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, David Geffen Sch Med, Los Angeles, CA USA.
20Univ Calif Los Angeles, Inst Precis Hlth, Los Angeles, CA USA.
21Fudan Univ, Fudan Univ Shanghai Canc Ctr, Sch Basic Med Sci, Dept Biochem & Mol Biol,Shanghai Med Coll, Shanghai, Peoples R China.
|Online Access:||PDF Full Text (PDF, 3 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2021051930603
|Publish Date:|| 2021-05-19
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.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work was supported by the Princess Margaret Cancer Foundation (886012001223 to H.H.H.), Canada Foundation for Innovation and Ontario Research Fund (CFI32372 to H.H.H.), NSERC discovery grant (498706 to H.H.H.), Canadian Cancer Society innovation grants (703800 to H.H.H.), Prostate Cancer Canada (TAG2018-2061, RS2016-1022, and D2016-1115 to H.H.H.), CIHR operating grants (142246, 152863, 152864, and 159567 to H.H.H., 153234 to M.L.), Terry Fox New Frontiers Program Project Grant (1090 P3 to H.H.H.) and the Ontario Institute for Cancer Research (Investigator Award to M.L.). H.H.H. was supported by TFRI New Investigator Awards and CIHR New Investigator Awards. H.H.H. holds an OMIR Early Researcher Award. S.R. was partially funded by the National Key R&D Plan of China Precision Medicine Project (2017YFC0908002) and the National Natural Science Foundation of China (81872105). G.-H.W. was partially supported by the grants from the Jane and Aatos Erkko Foundation, the Finnish Cancer Foundation, the Sigrid Juseliuksen Saatio, and the Fudan University Recruitment Grant. P.C.B. was supported by the NIH/NCI under award number P30CA016042. M.W. was partially suported by funding from National Institutes of Health under award numbers R01DK118946 and R01GM119189.
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