Global mapping of RNA N6-methyladenosine (m6A) in human subcutaneous and visceral adipose tissue reveals novel targets that correlate with clinical variables of obesity
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Bibliographic record
Abstract
Abstract Background Obesity is a major health challenge and fat accumulation in visceral depots is more strongly associated with metabolic comorbidities than deposition in subcutaneous depots. Epitranscriptomic regulation of gene expression by N 6 -methyladenosine (m 6 A) influences various aspects of RNA metabolism, however the m 6 A methylome in human adipose tissue and its relationship with fat distribution has not yet been investigated in detail. Methods In this study, we performed epitranscriptomic mapping of m 6 A in intra-individually paired samples of subcutaneous (SAT) and omental visceral adipose tissue (OVAT) from women with normal weight (BMI ≤25, n = 3) and obesity (BMI ≥35, n = 10) using meRIP-seq (discovery cohort). We further investigated differential m 6 A methylation for specific target genes in a larger cohort of individuals with obesity ( n = 72, validation cohort) using meRIP-qPCR. meRIP-seq was performed for primary adipocytes from a subset of the patients ( n = 4) to account for cell type specific differences. Results We here provide the first global map of m 6 A in human adipose tissue in paired samples of SAT and OVAT. We show an overall high overlap in m 6 A sites between individuals and depots, but also distinct depot-specific differences. We identify 339 target genes showing depot-specific m 6 A methylation. Depot-specific methylation was validated for selected sites in SEMA3A , SNAP47 and PPP1R9A in a larger validation cohort. We additionally identify differentially methylated targets between lean individuals and individuals with obesity, including TSC22D1 , FMNL2 and IL1R1 . By combining data from primary adipocytes with data from corresponding bulk adipose tissue, we identified a higher number of genes containing m 6 A in non-adipocyte cells in OVAT compared to SAT. Mechanistically, we show for selected targets that m 6 A affects RNA lifetime in pre-adipocyte cell culture models. Importantly, m 6 A methylation in selected targets correlates with clinically important variables related to obesity, fat distribution and glucose metabolism. Conclusions We identify a catalogue of novel targets showing adipose tissue depot specific m 6 A methylation, with potential as biomarkers in metabolic disease. Our findings underscore the regulatory role of m 6 A in obesity and provide valuable insights for future research. The datasets generated represent a significant resource for further insight in adipose tissue biology and its implications for metabolic health.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it