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Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes.
McAllan, Liam; Baranasic, Damir; Villicaña, Sergio; Brown, Scarlett; Zhang, Weihua; Lehne, Benjamin; Adamo, Marco; Jenkinson, Andrew; Elkalaawy, Mohamed; Mohammadi, Borzoueh; Hashemi, Majid; Fernandes, Nadia; Lambie, Nathalie; Williams, Richard; Christiansen, Colette; Yang, Youwen; Zudina, Liudmila; Lagou, Vasiliki; Tan, Sili; Castillo-Fernandez, Juan; King, James W D; Soong, Richie; Elliott, Paul; Scott, James; Prokopenko, Inga; Cebola, Inês; Loh, Marie; Lenhard, Boris; Batterham, Rachel L; Bell, Jordana T; Chambers, John C; Kooner, Jaspal S; Scott, William R.
Afiliação
  • McAllan L; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
  • Baranasic D; MRC London Institute of Medical Sciences, London, W12 0NN, UK.
  • Villicaña S; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
  • Brown S; MRC London Institute of Medical Sciences, London, W12 0NN, UK.
  • Zhang W; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
  • Lehne B; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
  • Adamo M; MRC London Institute of Medical Sciences, London, W12 0NN, UK.
  • Jenkinson A; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W2 1PG, UK.
  • Elkalaawy M; Department of Cardiology, Ealing Hospital, London North West University Healthcare NHS Trust, Middlesex, UB1 3HW, UK.
  • Mohammadi B; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W2 1PG, UK.
  • Hashemi M; UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London, NW1 2PG, UK.
  • Fernandes N; UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London, NW1 2PG, UK.
  • Lambie N; UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London, NW1 2PG, UK.
  • Williams R; UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London, NW1 2PG, UK.
  • Christiansen C; UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London, NW1 2PG, UK.
  • Yang Y; Imperial BRC Genomics Facility, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
  • Zudina L; Imperial BRC Genomics Facility, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
  • Lagou V; Imperial BRC Genomics Facility, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
  • Tan S; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
  • Castillo-Fernandez J; School of Mathematics and Statistics, Faculty of Science, Technology, Engineering and Mathematics, The Open University, Milton Keynes, UK.
  • King JWD; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W2 1PG, UK.
  • Soong R; School of Cardiovascular and Metabolic Medicine and Sciences, James Black Centre, King's College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, London, SE5 9NU, UK.
  • Elliott P; Department of Clinical & Experimental Medicine, University of Surrey, Guildford, UK.
  • Scott J; Department of Microbiology and Immunology, Laboratory of Adaptive Immunity, KU Leuven, Leuven, Belgium.
  • Prokopenko I; VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium.
  • Cebola I; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Loh M; Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
  • Lenhard B; MRC London Institute of Medical Sciences, London, W12 0NN, UK.
  • Batterham RL; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Bell JT; Department of Pathology, National University Hospital, Singapore, Singapore.
  • Chambers JC; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W2 1PG, UK.
  • Kooner JS; MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
  • Scott WR; National Institute for Health Research Biomedical Research Centre, Imperial College London, London, UK.
Nat Commun ; 14(1): 2784, 2023 05 15.
Article em En | MEDLINE | ID: mdl-37188674
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 < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Metilação de DNA / Diabetes Mellitus Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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XML
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Metilação de DNA / Diabetes Mellitus Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article