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April 21st, 2025
Version: 2
University of Oslo
molecular biology
biorxiv

Transient SUMOylation Inhibition Induces Stable Epigenetic Beiging Fate In Human White Adipocytes

Nothnagel, P. M.Open in Google Scholar•Briand, N.Open in Google Scholar•Wik, J. A.Open in Google Scholar•Strom, Y. E.Open in Google Scholar•Bjoras, M.Open in Google Scholar•Enserink, J. M.Open in Google Scholar•Skalhegg, B. S.Open in Google Scholar•Mathelier, A.Open in Google Scholar•Chymkowitch, P.Open in Google Scholar

Emerging evidence suggests that transient epigenomic deregulation can establish stable cancer- or obesity-associated epigenetic fates, highlighting the need to understand mechanisms that sustain epigenetic stability. The small ubiquitin-like modifier (SUMO) regulates stemness, differentiation, and chromatin identity and has been implicated in tumorigenesis. Here, we investigate SUMOylation's role in epigenetic memory using the SUMOylation inhibitor TAK-981 (Subasumstat) and adipogenesis as a model. We show that transient SUMOylation inhibition in human adipose stem cells and mature adipocytes induces stable reprogramming of white adipocytes into beige adipocytes in a rosiglitazone-dependent manner. This reprogramming irreversibly upregulates the cAMP-PKA-p38 axis and stably remodels PPARG and PPARA enhancers, establishing a lasting epigenetic beiging fate characterized by upregulation of beiging genes, including UCP1, which induces mitochondrial uncoupling. SUMOylation is thus a key barrier to adipocyte reprogramming limiting both de novo beige adipocyte differentiation and white-to-beige transdifferentiation. Our data also suggest that combining TAK-981 with PPARG agonists could promote sustained, metabolically beneficial adipose tissue remodeling.

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