Increased body mass index is linked to systemic inflammation through altered chromatin co-accessibility in human preadipocytes [ATAC-Seq]

Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins’ preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset (~88.5Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions. To investigate the effects of increased body mass index (BMI) on preadipocyte genomic programming, we isolated and cultured preadipocytes from the subcutaneous adipose biopsies of BMI-discordant monozygotic (MZ) twins. We performed chromatin accessibility profiling analysis from ATAC-seq data produced from the preadipocytes of 10 pairs (n=20) of BMI-discordant MZ twins. We initiated the adipogenic differentiation of the preadipocytes and collected ATAC-seq data from 9 pairs (n=18) of the same BMI-discordant MZ twins (one pair failed the differentiation). * Submitter declares that the raw data were not deposited due to privacy concerns