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CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer.
Ahmed, Musaddeque; Soares, Fraser; Xia, Ji-Han; Yang, Yue; Li, Jing; Guo, Haiyang; Su, Peiran; Tian, Yijun; Lee, Hyung Joo; Wang, Miranda; Akhtar, Nayeema; Houlahan, Kathleen E; Bosch, Almudena; Zhou, Stanley; Mazrooei, Parisa; Hua, Junjie T; Chen, Sujun; Petricca, Jessica; Zeng, Yong; Davies, Alastair; Fraser, Michael; Quigley, David A; Feng, Felix Y; Boutros, Paul C; Lupien, Mathieu; Zoubeidi, Amina; Wang, Liang; Walsh, Martin J; Wang, Ting; Ren, Shancheng; Wei, Gong-Hong; He, Housheng Hansen.
Afiliação
  • Ahmed M; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Soares F; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Xia JH; Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
  • Yang Y; Changhai Hospital, Shanghai, China.
  • Li J; Changhai Hospital, Shanghai, China.
  • Guo H; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Su P; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Tian Y; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Lee HJ; Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • Wang M; Department of Genetics, Washington University in St. Louis, St. Louis, MO, USA.
  • Akhtar N; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Houlahan KE; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Bosch A; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Zhou S; Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • Mazrooei P; Vector Institute, Toronto, ON, Canada.
  • Hua JT; Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Chen S; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Petricca J; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Zeng Y; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Davies A; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Fraser M; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Quigley DA; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Feng FY; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Boutros PC; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Lupien M; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Zoubeidi A; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Wang L; Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • Walsh MJ; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Wang T; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • Ren S; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
  • Wei GH; The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, BC, Canada.
  • He HH; Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
Nat Commun ; 12(1): 1781, 2021 03 19.
Article em En | MEDLINE | ID: mdl-33741908
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Metilação de DNA / Predisposição Genética para Doença / Estudo de Associação Genômica Ampla / Sistemas CRISPR-Cas / Edição de Genes Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Animals / Humans / Male Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Canadá País de publicação: Reino Unido
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Metilação de DNA / Predisposição Genética para Doença / Estudo de Associação Genômica Ampla / Sistemas CRISPR-Cas / Edição de Genes Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Animals / Humans / Male Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Canadá País de publicação: Reino Unido