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Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes

Author

Listed:
  • Liam McAllan

    (Imperial College London
    MRC London Institute of Medical Sciences)

  • Damir Baranasic

    (Imperial College London
    MRC London Institute of Medical Sciences)

  • Sergio Villicaña

    (King’s College London)

  • Scarlett Brown

    (Imperial College London
    MRC London Institute of Medical Sciences)

  • Weihua Zhang

    (School of Public Health, Imperial College London
    Ealing Hospital, London North West University Healthcare NHS Trust)

  • Benjamin Lehne

    (School of Public Health, Imperial College London)

  • Marco Adamo

    (University College London Hospitals, Ground Floor West Wing)

  • Andrew Jenkinson

    (University College London Hospitals, Ground Floor West Wing)

  • Mohamed Elkalaawy

    (University College London Hospitals, Ground Floor West Wing)

  • Borzoueh Mohammadi

    (University College London Hospitals, Ground Floor West Wing)

  • Majid Hashemi

    (University College London Hospitals, Ground Floor West Wing)

  • Nadia Fernandes

    (Faculty of Medicine, Imperial College London)

  • Nathalie Lambie

    (Faculty of Medicine, Imperial College London)

  • Richard Williams

    (Faculty of Medicine, Imperial College London)

  • Colette Christiansen

    (King’s College London
    Faculty of Science, Technology, Engineering and Mathematics, The Open University)

  • Youwen Yang

    (School of Public Health, Imperial College London
    King’s College London British Heart Foundation Centre of Excellence)

  • Liudmila Zudina

    (University of Surrey)

  • Vasiliki Lagou

    (KU Leuven
    VIB-KU Leuven Center for Brain and Disease Research)

  • Sili Tan

    (National University of Singapore)

  • Juan Castillo-Fernandez

    (King’s College London)

  • James W. D. King

    (MRC London Institute of Medical Sciences)

  • Richie Soong

    (National University of Singapore
    National University Hospital)

  • Paul Elliott

    (School of Public Health, Imperial College London
    School of Public Health, Imperial College London
    Imperial College London)

  • James Scott

    (Imperial College London
    Imperial College Healthcare NHS Trust)

  • Inga Prokopenko

    (University of Surrey
    University of Surrey
    Ufa Federal Research Centre Russian Academy of Sciences)

  • Inês Cebola

    (Imperial College London)

  • Marie Loh

    (School of Public Health, Imperial College London
    Agency for Science, Technology and Research (A*STAR)
    Nanyang Technological University)

  • Boris Lenhard

    (Imperial College London
    MRC London Institute of Medical Sciences)

  • Rachel L. Batterham

    (University College London Hospitals, Ground Floor West Wing
    University College
    National Institute of Health Research University College London Hospitals Biomedical Research Centre)

  • Jordana T. Bell

    (King’s College London)

  • John C. Chambers

    (School of Public Health, Imperial College London
    Ealing Hospital, London North West University Healthcare NHS Trust
    School of Public Health, Imperial College London
    Imperial College Healthcare NHS Trust)

  • Jaspal S. Kooner

    (Ealing Hospital, London North West University Healthcare NHS Trust
    School of Public Health, Imperial College London
    Imperial College London
    Imperial College Healthcare NHS Trust)

  • William R. Scott

    (Imperial College London
    MRC London Institute of Medical Sciences
    School of Public Health, Imperial College London
    Imperial College Healthcare NHS Trust)

Abstract

DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P 500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.

Suggested Citation

  • Liam McAllan & Damir Baranasic & Sergio Villicaña & Scarlett Brown & Weihua Zhang & Benjamin Lehne & Marco Adamo & Andrew Jenkinson & Mohamed Elkalaawy & Borzoueh Mohammadi & Majid Hashemi & Nadia Fer, 2023. "Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38439-z
    DOI: 10.1038/s41467-023-38439-z
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