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

Liam McAllan; Damir Baranasic; Sergio Villicaña; Scarlett Brown; Weihua Zhang; Benjamin Lehne; Marco Adamo; Andrew Jenkinson; Mohamed Elkalaawy; Borzoueh Mohammadi; Majid Hashemi; Nadia Fernandes; Nathalie Lambie; Richard Williams; Colette Christiansen; Youwen Yang; Liudmila Zudina; Vasiliki Lagou; Sili Tan; Juan Castillo-Fernandez; James W.D. King; Richie Soong; Paul Elliott; James Scott; Inga Prokopenko; Inês Cebola; Marie Loh; Boris Lenhard; Rachel L. Batterham; Jordana T. Bell; John C. Chambers; Jaspal S. Kooner; William R. Scott

doi:10.1038/s41467-023-38439-z

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

Liam McAllan
, Damir Baranasic
, Sergio Villicaña
, Scarlett Brown
, Weihua Zhang
, Benjamin Lehne
, Marco Adamo
, Andrew Jenkinson
, Mohamed Elkalaawy
, Borzoueh Mohammadi
, Majid Hashemi
, Nadia Fernandes
, Nathalie Lambie
, Richard Williams
, Colette Christiansen
, Youwen Yang
, Liudmila Zudina
, Vasiliki Lagou
, Sili Tan
, Juan Castillo-Fernandez

James W.D. King, Richie Soong, Paul Elliott, James Scott, Inga Prokopenko, Inês Cebola, Marie Loh, Boris Lenhard, Rachel L. Batterham, Jordana T. Bell, John C. Chambers, Jaspal S. Kooner, William R. Scott^*

^*Corresponding author for this work

Twin Research & Genetic Epidemiology

Imperial College London
MRC Medical Research Council
King's College London
Ealing Hospital NHS Trust
UCL Hospitals NHS Foundation Trust
NIHR Imperial Biomedical Research Centre
Open University
University of Surrey
KU Leuven
Cancer Science Institute of Singapore
National University Hospital, Singapore
MRC-PHE Centre for Environmental & Health
Queens Medical Centre
National Heart and Lung Institute
Institute of Biochemistry and Genetics, Ufa Scientific Center RAS
A*STAR Agency for Science, Technology and Research
Department of Metabolic Medicine Lee Kong Chian School of Medicine
UCL University College London

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

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.

Original language	English
Article number	2784
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-38439-z
Publication status	Published - Dec 2023

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SDG 3 Good Health and Well-being

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10.1038/s41467-023-38439-z

Cite this

McAllan, L., Baranasic, D., Villicaña, S., Brown, S., Zhang, W., Lehne, B., Adamo, M., Jenkinson, A., Elkalaawy, M., Mohammadi, B., Hashemi, M., Fernandes, N., Lambie, N., Williams, R., Christiansen, C., Yang, Y., Zudina, L., Lagou, V., Tan, S., ... Scott, W. R. (2023). Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes. Nature Communications, 14(1), Article 2784. https://doi.org/10.1038/s41467-023-38439-z

@article{792b8955ce3c441f9818a3bfeaaf1d63,

title = "Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes",

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.",

author = "Liam McAllan and Damir Baranasic and Sergio Villica{\~n}a and Scarlett Brown and Weihua Zhang and Benjamin Lehne and Marco Adamo and Andrew Jenkinson and Mohamed Elkalaawy and Borzoueh Mohammadi and Majid Hashemi and Nadia Fernandes and Nathalie Lambie and Richard Williams and Colette Christiansen and Youwen Yang and Liudmila Zudina and Vasiliki Lagou and Sili Tan and Juan Castillo-Fernandez and King, \{James W.D.\} and Richie Soong and Paul Elliott and James Scott and Inga Prokopenko and In{\^e}s Cebola and Marie Loh and Boris Lenhard and Batterham, \{Rachel L.\} and Bell, \{Jordana T.\} and Chambers, \{John C.\} and Kooner, \{Jaspal S.\} and Scott, \{William R.\}",

note = "Funding Information: This work was funded by the Medical Research Council UK (MR/K002414/1, W.R.S.), the Wellcome Trust (219602/Z/19/Z, W.R.S.) and the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC, W.R.S.). The Illumina HumanMethylation450 Beadchip data used in this research was generated by the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z). The Illumina EPIC Beadchip data were generated in collaboration with R.S., funded by the European Union FP7 (EpiMigrant, 279143, J.C.C.). The Imperial BRC Genomics Facility (supported by NIHR funding to the Imperial Biomedical Research Centre) provided resources and support that contributed to the RNA sequencing and targeted methylation sequencing results. The TwinsUK research components were funded by JPI ERA-HDHL DIMENSION via the Biotechnology and Biological Sciences Research Council (BB/S020845/1, J.T.B.). TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the NIHR-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London (J.T.B.). R.L.B. received funding from National Institute for Health and Care Research (RP-2015-06-005), Sir Jules Thorn Charitable Trust (Biomedical Research Award) and Rosetrees Trust and Robert Luff Foundation grant CM710. D.B. was awarded a NPIF Rutherford Fellowship (MC\_EX\_MR/S300007/1). I.C. is recipient of a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (224662/Z/21/Z). I.P., L.Z. and V.L. were funded in part by the Diabetes UK (BDA number: 20/0006307), the European Union{\textquoteright}s Horizon 2020 research and innovation programme (LONGITOOLS, H2020-SC1-2019-874739), Agence Nationale de la Recherche (PreciDIAB, ANR-18-IBHU-0001), by the European Union through the “Fonds europ{\'e}en de d{\'e}veloppement regional” (FEDER), by the “Conseil R{\'e}gional des Hauts-de-France” (Hauts-de-France Regional Council) and by the “M{\'e}tropole Europ{\'e}enne de Lille” (MEL, European Metropolis of Lille). For the purpose of open access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We thank the participants and research staff who made this possible. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-38439-z",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

McAllan, L, Baranasic, D, Villicaña, S, Brown, S, Zhang, W, Lehne, B, Adamo, M, Jenkinson, A, Elkalaawy, M, Mohammadi, B, Hashemi, M, Fernandes, N, Lambie, N, Williams, R, Christiansen, C, Yang, Y, Zudina, L, Lagou, V, Tan, S, Castillo-Fernandez, J, King, JWD, Soong, R, Elliott, P, Scott, J, Prokopenko, I, Cebola, I, Loh, M, Lenhard, B, Batterham, RL, Bell, JT, Chambers, JC, Kooner, JS & Scott, WR 2023, 'Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes', Nature Communications, vol. 14, no. 1, 2784. https://doi.org/10.1038/s41467-023-38439-z

TY - JOUR

T1 - Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes

AU - McAllan, Liam

AU - Baranasic, Damir

AU - Villicaña, Sergio

AU - Brown, Scarlett

AU - Zhang, Weihua

AU - Lehne, Benjamin

AU - Adamo, Marco

AU - Jenkinson, Andrew

AU - Elkalaawy, Mohamed

AU - Mohammadi, Borzoueh

AU - Hashemi, Majid

AU - Fernandes, Nadia

AU - Lambie, Nathalie

AU - Williams, Richard

AU - Christiansen, Colette

AU - Yang, Youwen

AU - Zudina, Liudmila

AU - Lagou, Vasiliki

AU - Tan, Sili

AU - Castillo-Fernandez, Juan

AU - King, James W.D.

AU - Soong, Richie

AU - Elliott, Paul

AU - Scott, James

AU - Prokopenko, Inga

AU - Cebola, Inês

AU - Loh, Marie

AU - Lenhard, Boris

AU - Batterham, Rachel L.

AU - Bell, Jordana T.

AU - Chambers, John C.

AU - Kooner, Jaspal S.

AU - Scott, William R.

N1 - Funding Information: This work was funded by the Medical Research Council UK (MR/K002414/1, W.R.S.), the Wellcome Trust (219602/Z/19/Z, W.R.S.) and the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC, W.R.S.). The Illumina HumanMethylation450 Beadchip data used in this research was generated by the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z). The Illumina EPIC Beadchip data were generated in collaboration with R.S., funded by the European Union FP7 (EpiMigrant, 279143, J.C.C.). The Imperial BRC Genomics Facility (supported by NIHR funding to the Imperial Biomedical Research Centre) provided resources and support that contributed to the RNA sequencing and targeted methylation sequencing results. The TwinsUK research components were funded by JPI ERA-HDHL DIMENSION via the Biotechnology and Biological Sciences Research Council (BB/S020845/1, J.T.B.). TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the NIHR-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London (J.T.B.). R.L.B. received funding from National Institute for Health and Care Research (RP-2015-06-005), Sir Jules Thorn Charitable Trust (Biomedical Research Award) and Rosetrees Trust and Robert Luff Foundation grant CM710. D.B. was awarded a NPIF Rutherford Fellowship (MC_EX_MR/S300007/1). I.C. is recipient of a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (224662/Z/21/Z). I.P., L.Z. and V.L. were funded in part by the Diabetes UK (BDA number: 20/0006307), the European Union’s Horizon 2020 research and innovation programme (LONGITOOLS, H2020-SC1-2019-874739), Agence Nationale de la Recherche (PreciDIAB, ANR-18-IBHU-0001), by the European Union through the “Fonds européen de développement regional” (FEDER), by the “Conseil Régional des Hauts-de-France” (Hauts-de-France Regional Council) and by the “Métropole Européenne de Lille” (MEL, European Metropolis of Lille). For the purpose of open access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We thank the participants and research staff who made this possible. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85159437073

U2 - 10.1038/s41467-023-38439-z

DO - 10.1038/s41467-023-38439-z

M3 - Article

C2 - 37188674

AN - SCOPUS:85159437073

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2784

ER -

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

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