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

Author

Listed:
  • 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
    University of Toronto)

  • 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
    Ontario Institute for Cancer Research
    Vector Institute
    University of California, Los Angeles)

  • Almudena Bosch

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Stanley Zhou

    (Princess Margaret Cancer Center/University Health Network
    University of Toronto)

  • Parisa Mazrooei

    (Princess Margaret Cancer Center/University Health Network
    University of Toronto)

  • Junjie T. Hua

    (Princess Margaret Cancer Center/University Health Network
    University of Toronto)

  • Sujun Chen

    (Princess Margaret Cancer Center/University Health Network
    University of Toronto
    Ontario Institute for Cancer Research)

  • Jessica Petricca

    (Princess Margaret Cancer Center/University Health Network
    University of Toronto)

  • 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
    Ontario Institute for Cancer Research)

  • David A. Quigley

    (University of California at San Francisco
    University of California at San Francisco)

  • Felix Y. Feng

    (University of California at San Francisco
    University of California at San Francisco
    University of California at San Francisco
    University of California at San Francisco)

  • Paul C. Boutros

    (Vector Institute
    University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Mathieu Lupien

    (Princess Margaret Cancer Center/University Health Network
    University of Toronto
    Ontario Institute for Cancer Research)

  • 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
    Icahn School of Medicine at Mount Sinai)

  • Ting Wang

    (Washington University in St. Louis)

  • Shancheng Ren

    (Changhai Hospital)

  • Gong-Hong Wei

    (University of Oulu
    Shanghai Medical College of Fudan University)

  • Housheng Hansen He

    (Princess Margaret Cancer Center/University Health Network
    University of Toronto)

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.

Suggested Citation

  • 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 & Stan, 2021. "CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21867-0
    DOI: 10.1038/s41467-021-21867-0
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    Cited by:

    1. Jie Liu & Xuehua Zhong, 2024. "Epiallelic variation of non-coding RNA genes and their phenotypic consequences," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Zhao Wei & Song Wang & Yaning Xu & Wenzheng Wang & Fraser Soares & Musaddeque Ahmed & Ping Su & Tingting Wang & Elias Orouji & Xin Xu & Yong Zeng & Sujun Chen & Xiaoyu Liu & Tianwei Jia & Zhaojian Liu, 2023. "MYC reshapes CTCF-mediated chromatin architecture in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Nikolaos Giannareas & Qin Zhang & Xiayun Yang & Rong Na & Yijun Tian & Yuehong Yang & Xiaohao Ruan & Da Huang & Xiaoqun Yang & Chaofu Wang & Peng Zhang & Aki Manninen & Liang Wang & Gong-Hong Wei, 2022. "Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    4. Theodore Sakellaropoulos & Catherine Do & Guimei Jiang & Giulia Cova & Peter Meyn & Dacia Dimartino & Sitharam Ramaswami & Adriana Heguy & Aristotelis Tsirigos & Jane A. Skok, 2024. "MethNet: a robust approach to identify regulatory hubs and their distal targets from cancer data," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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