Abstract
Recent studies indicate that transient deregulation of the epigenome is sufficient to establish a stable epigenetic cancer fate or induce an epigenetic obesogenic memory in absence of DNA mutations. These findings emphasize the need for detailed investigation into the mechanisms sustaining epigenetic fate stability.
SUMOylation plays a pivotal role in regulating stemness, differentiation, and cellular identity at the chromatin level. Consistently, SUMOylation has been shown to promote cellular transformation, tumor stemness, and metastasis.
We employed the SUMOylation inhibitor TAK-981 (Subasumstat) and adipogenesis as a model system to explore the role of SUMOylation in maintaining epigenetic memory. We found that transient inhibition of SUMOylation in human pre-adipocytes induces stable chromatin remodeling and activation of specific enhancers and transcription factors, resulting in hyper-adipogenic transcription and excessive fat accumulation. We also found that transient SUMOylation inhibition facilitates rosiglitazone-dependent reprogramming of white adipocytes into beige adipocytes, a metabolically favorable process in which fat storage shifts to fat utilization for thermogenesis. Finally, boosting SUMOylation in mouse beige adipocyte precursors promotes osteogenesis over adipogenesis.
In conclusion, SUMOylation safeguards cellular homeostasis by preserving the epigenetic fate of adipose stem cells and restricting adipocyte reprogramming. These findings indicate that the adipogenic, osteogenic and beiging potential of adipocytes is regulated by SUMOylation, providing an epigenetic basis for individual variability in fat accumulation. More broadly, SUMOylation in progenitor cells is preventing epigenetic drift, which may protect from disease states such as obesity, metabolic disorders and cancer.