Chromatin landscape in paired human visceral and subcutaneous adipose tissue and its impact on clinical variables in obesity.

Abstract

Obesity is a global health challenge and adipose tissue exhibits distinct depot-specific characteristics impacting differentially on the risk of metabolic comorbidities. Here, we integrate chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) data from intra-individually paired human subcutaneous (SAT) and omental visceral adipose tissue (OVAT) samples to unveil depot-specific regulatory mechanisms. We identified twice as many depot-specific differentially accessible regions (DARs) in OVAT compared to SAT. SAT-specific regions showed enrichment for adipose tissue enhancers involving genes controlling extracellular matrix organization and metabolic processes. In contrast, OVAT-specific regions showed enrichment in promoters linked to genes associated with cardiomyopathies. Moreover, OVAT-specific regions were enriched for bivalent transcription start site and repressive chromatin states, suggesting a "lingering" regulatory state. Motif analysis identified CTCF and BACH1 as most significantly enriched motifs in SAT and OVAT-specific DARs, respectively. Distinct gene sets correlated with important clinical variables of obesity, fat distribution measures, as well as insulin, glucose, and lipid metabolism. We provide an integrated analysis of chromatin accessibility and transcriptional profiles in paired human SAT and OVAT samples, offering new insights into the regulatory landscape of adipose tissue and highlighting depot-specific mechanisms in obesity pathogenesis. SS received EU-Scientia postdoctoral Fellowship and project funding from the European Union's Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie Grant, (agreement No. 801133). LlCP and TR were supported by Helse Sør-Øst grants to Y.B (ID 2017079, ID 278908). MB received funding from grants from the DFG (German Research Foundation)-Projekt number 209933838-SFB 1052 (project B1) and by Deutsches Zentrum für Diabetesforschung (DZD, Grant: 82DZD00601).