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Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics

Author

Listed:
  • Helen E. Speedy

    (Institute of Cancer Research)

  • Renée Beekman

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC))

  • Vicente Chapaprieta

    (Universitat de Barcelona)

  • Giulia Orlando

    (Institute of Cancer Research)

  • Philip J. Law

    (Institute of Cancer Research)

  • David Martín-García

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC))

  • Jesús Gutiérrez-Abril

    (Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Daniel Catovsky

    (Institute of Cancer Research)

  • Sílvia Beà

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC))

  • Guillem Clot

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC))

  • Montserrat Puiggròs

    (Universitat de Barcelona)

  • David Torrents

    (Universitat de Barcelona
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Xose S. Puente

    (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • James M. Allan

    (Newcastle University)

  • Carlos López-Otín

    (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Elias Campo

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    Universitat de Barcelona
    Hospital Clinic of Barcelona)

  • Richard S. Houlston

    (Institute of Cancer Research)

  • José I. Martín-Subero

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    Universitat de Barcelona
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

Abstract

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL.

Suggested Citation

  • Helen E. Speedy & Renée Beekman & Vicente Chapaprieta & Giulia Orlando & Philip J. Law & David Martín-García & Jesús Gutiérrez-Abril & Daniel Catovsky & Sílvia Beà & Guillem Clot & Montserrat Puiggròs, 2019. "Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11582-2
    DOI: 10.1038/s41467-019-11582-2
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    Cited by:

    1. Alexandros Armaos & François Serra & Iker Núñez-Carpintero & Ji-Heui Seo & Sylvan C. Baca & Stefano Gustincich & Alfonso Valencia & Matthew L. Freedman & Davide Cirillo & Claudia Giambartolomei & Gian, 2023. "The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Gerard Llimos & Vincent Gardeux & Ute Koch & Judith F. Kribelbauer & Antonina Hafner & Daniel Alpern & Joern Pezoldt & Maria Litovchenko & Julie Russeil & Riccardo Dainese & Riccardo Moia & Abdurraouf, 2022. "A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    3. Laureano Tomás-Daza & Llorenç Rovirosa & Paula López-Martí & Andrea Nieto-Aliseda & François Serra & Ainoa Planas-Riverola & Oscar Molina & Rebecca McDonald & Cedric Ghevaert & Esther Cuatrecasas & Do, 2023. "Low input capture Hi-C (liCHi-C) identifies promoter-enhancer interactions at high-resolution," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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