Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 05 2023
15 05 2023
Historique:
received:
13
10
2021
accepted:
03
05
2023
medline:
17
5
2023
pubmed:
16
5
2023
entrez:
15
5
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37188674
doi: 10.1038/s41467-023-38439-z
pii: 10.1038/s41467-023-38439-z
pmc: PMC10185556
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2784Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S020845/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 219602/Z/19/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 212945/Z/18/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1102/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 090532/Z/09/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 224662/Z/21/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K002414/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_EX_MR/S300007/1
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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