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bioRxiv · 10.1101/2025.03.07.642034

SUMOylation Restricts Adaptive Thermogenesis by Suppressing Beiging Gene Networks

Nothnagel, P. M.·Briand, N.·Wik, J. A.·Strom, Y. E.·Bjoras, M.·Enserink, J. M.·Skalhegg, B. S.·Mathelier, A.·Chymkowitch, P.
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Abstract

SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how transient perturbation of the SUMO pathway impacts adipocyte plasticity remains unclear. Here we show that brief pharmacologic inhibition of SUMO conjugation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure before adipogenic induction produces long-lasting changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and transcription factor footprinting revealed immediate and durable chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements within key thermogenic enhancers, with increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling, and stabilization of beiging transcriptional activators. Our data support a model in which transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic, cell type specific reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/642034v3_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@9efd29org.highwire.dtl.DTLVardef@1fecda3org.highwire.dtl.DTLVardef@16eb784org.highwire.dtl.DTLVardef@1d25683_HPS_FORMAT_FIGEXP M_FIG C_FIG SUMOylation restricts de novo differentiation of pre-adipocytes into beige adipocytes by repressing cAMP signaling and preventing epigenetic and transcriptional reprogramming of white adipocytes.

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Nothnagel, P. M., Briand, N., Wik, J. A., Strom, Y. E., Bjoras, M., Enserink, J. M., Skalhegg, B. S., Mathelier, A., Chymkowitch, P.. 2025-03-11. SUMOylation Restricts Adaptive Thermogenesis by Suppressing Beiging Gene Networks. https://doi.org/10.1101/2025.03.07.642034

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