Abstract
BackgroundN6-methyladenosine (m6A) is one of the most abundant post-transcriptional modifications on mRNA influencing mRNA metabolism. There is emerging evidence for its implication in metabolic disease. No comprehensive analyses on gene expression of m6A regulators in human adipose tissue, especially in paired adipose tissue depots, and its correlation with clinical variables were reported so far. We hypothesized that inter-depot specific gene expression of m6A regulators may differentially correlate with clinical variables related to obesity and fat distribution.MethodsWe extracted intra-individually paired gene expression data (omental visceral adipose tissue (OVAT) N=48; subcutaneous adipose tissue (SAT) N=56) of m6A regulators from an existing microarray dataset. We also measured gene expression in another sample set of paired OVAT and SAT (N=46) using RT-qPCR. Finally, we extracted existing gene expression data from peripheral mononuclear blood cells (PBMCs) and single nucleotide polymorphisms (SNPs) in METTL3 and YTHDF3 from genome wide data from the Sorbs population (N=1049). The data were analysed for differential gene expression between OVAT and SAT; and for association with obesity and clinical variables. We further tested for association of SNP markers with gene expression and clinical traits.ResultsIn adipose tissue we observed that several m6A regulators (WTAP, VIRMA, YTHDC1 and ALKBH5) correlate with obesity and clinical variables. Moreover, we found adipose tissue depot specific gene expression for METTL3, WTAP, VIRMA, FTO and YTHDC1. In PBMCs, we identified ALKBH5 and YTHDF3 correlated with obesity. Genetic markers in METTL3 associate with BMI whilst SNPs in YTHDF3 are associated with its gene expression.ConclusionsOur data show that expression of m6A regulators correlates with obesity, is adipose tissue depot-specific and related to clinical traits. Genetic variation in m6A regulators adds an additional layer of variability to the functional consequences.
Highlights
Obesity is a major health burden predisposing to a variety of serious co-morbidities including metabolic disorders [1]
In omental visceral adipose tissue (OVAT), we identified by using independent t-tests or Mann-Whitney-U tests, the writers Wilms tumor 1-associated protein (WTAP) (ILMN_2279339; P=0.011) and vir like m6A methyltransferase associated (VIRMA) (P=0.028) as differentially expressed between lean and obese (Table 2)
Among non-diabetic individuals we find that gene expression of WTAP in OVAT correlates with body mass index (BMI) (P=0.003) and waist circumference (P=0.009)
Summary
Obesity is a major health burden predisposing to a variety of serious co-morbidities including metabolic disorders [1]. Multiple “reader” proteins including YTH family proteins and insulin like growth factor 2 binding proteins (IGF2BPs) are responsible for translating m6A deposition into function [12] Readers such as YTHDF2 and YTHDF3 increase transcript decay, while in contrast IGFBPs (IGF2BP1, 2 and 3) function by stabilizing mRNA. To the best of our knowledge, no attempts have been undertaken to investigate the role of m6A regulators in intraindividually paired samples of human visceral vs subcutaneous adipose tissue, their role in obesity and potential differential depot-specific correlation with anthropometric and metabolic traits. We set out to describe (i) the gene expression profile of m6A writers, readers and erasers in visceral vs subcutaneous adipose tissue with a potential depot-specificity perspective; (ii) to analyze its relationship to clinically relevant traits of obesity in several well-described cohorts and (iii) to test whether SNP markers in m6A regulators associate with gene expression and clinical traits. We hypothesized that inter-depot specific gene expression of m6A regulators may differentially correlate with clinical variables related to obesity and fat distribution
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