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; Housheng Hansen He

doi:10.1038/s41467-021-21867-0

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 DaviesMichael 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, Housheng Hansen He

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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.

Original language	English
Article number	1781
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21867-0
State	Published - Dec 1 2021

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Ahmed, M., Soares, F., Xia, J. H., Yang, Y., Li, J., Guo, H., Su, P., Tian, Y., Lee, H. J., Wang, M., Akhtar, N., Houlahan, K. E., Bosch, A., Zhou, S., Mazrooei, P., Hua, J. T., Chen, S., Petricca, J., Zeng, Y., ... He, H. H. (2021). CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer. Nature communications, 12(1), Article 1781. https://doi.org/10.1038/s41467-021-21867-0

@article{3ea802520c644386b7f8acba52e37fad,

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

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.",

author = "Musaddeque Ahmed and Fraser Soares and Xia, {Ji Han} and Yue Yang and Jing Li and Haiyang Guo and Peiran Su and Yijun Tian and Lee, {Hyung Joo} and Miranda Wang and Nayeema Akhtar and Houlahan, {Kathleen E.} and Almudena Bosch and Stanley Zhou and Parisa Mazrooei and Hua, {Junjie T.} and Sujun Chen and Jessica Petricca and Yong Zeng and Alastair Davies and Michael Fraser and Quigley, {David A.} and Feng, {Felix Y.} and Boutros, {Paul C.} and Mathieu Lupien and Amina Zoubeidi and Liang Wang and Walsh, {Martin J.} and Ting Wang and Shancheng Ren and Wei, {Gong Hong} and He, {Housheng Hansen}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-21867-0",

language = "English",

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Ahmed, M, Soares, F, Xia, JH, Yang, Y, Li, J, Guo, H, Su, P, Tian, Y, Lee, HJ, Wang, M, Akhtar, N, Houlahan, KE, Bosch, A, Zhou, S, Mazrooei, P, Hua, JT, Chen, S, Petricca, J, Zeng, Y, Davies, A, Fraser, M, Quigley, DA, Feng, FY, Boutros, PC, Lupien, M, Zoubeidi, A, Wang, L, Walsh, MJ, Wang, T, Ren, S, Wei, GH & He, HH 2021, 'CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer', Nature communications, vol. 12, no. 1, 1781. https://doi.org/10.1038/s41467-021-21867-0

TY - JOUR

T1 - 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

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85102857389&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-21867-0

DO - 10.1038/s41467-021-21867-0

M3 - Article

C2 - 33741908

AN - SCOPUS:85102857389

SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1781

ER -

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

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