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

Kristina M. Garske, Asha Kar, Caroline Comenho, Brunilda Balliu, David Z. Pan, Yash V. Bhagat, Gregory Rosenberg, Amogha Koka, Sankha Subhra Das, Zong Miao, Janet S. Sinsheimer, Jaakko Kaprio, Kirsi H. Pietiläinen and Päivi Pajukanta ()
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Kristina M. Garske: David Geffen School of Medicine at UCLA
Asha Kar: David Geffen School of Medicine at UCLA
Caroline Comenho: David Geffen School of Medicine at UCLA
Brunilda Balliu: UCLA
David Z. Pan: David Geffen School of Medicine at UCLA
Yash V. Bhagat: David Geffen School of Medicine at UCLA
Gregory Rosenberg: David Geffen School of Medicine at UCLA
Amogha Koka: David Geffen School of Medicine at UCLA
Sankha Subhra Das: David Geffen School of Medicine at UCLA
Zong Miao: David Geffen School of Medicine at UCLA
Janet S. Sinsheimer: David Geffen School of Medicine at UCLA
Jaakko Kaprio: Institute for Molecular Medicine Finland (FIMM), University of Helsinki
Kirsi H. Pietiläinen: University of Helsinki
Päivi Pajukanta: David Geffen School of Medicine at UCLA

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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 ( ~ 88.5 Mb) 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.

Date: 2023
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DOI: 10.1038/s41467-023-39919-y

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