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

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<1x10-7). 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.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001010195	94 human adipocyte samples isolated from whole adipose tissues using collagenase digestion of tissue and flotation of lipid-laden adipocytes, followed by RNA isolation and RNA sequencing (SMARTer Stranded Total RNA-Seq library preparation, HiSeq 4000 100-bp paired-end reads). Adipocyte samples comprise subcutaneous and visceral adipocytes isolated from obese and lean people (N=24 obese-subcutaneous, N=24 obese-visceral, N=22 control-subcutaneous, N=24 control-visceral). Human adipocyte RNA sequencing data are provided as BAM files.	Illumina HiSeq 4000	93

Publications	Citations
Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes. 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. Nat Commun 14: 2023 2784	6

Publications

Citations

Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes.
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. Nat Commun 14: 2023 2784