SETD6-mediated methylation of PPARγ establishes a transcriptional feedback circuit promoting lipid accumulation in liver-derived cells.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key transcriptional regulator of genes mediating adipogenesis (fat-cell differentiation), and lipid storage in several cell types like hepatocytes. As such, its regulation is crucial for cell and organismal physiology. Indeed, PPARγ's activity is regulated by multiple mechanisms, including post-transcriptional modifications, which, when dys-coordinated, may contribute to the pathogenesis of various states, including obesity, insulin resistance, and fatty liver disease. Here, we demonstrate that SETD6 binds to and methylates PPARγ at lysine 170 (K170) both in vitro and in liver-derived cells. This methylation event, in turn, is required for PPARγ-mediated activation of SETD6 transcription via promoter binding, forming a positive feedback regulatory loop. RNA-sequencing revealed that both SETD6 and PPARγ methylation at K170 are required for full induction of lipid metabolism genes' expression, manifesting functionally in lipid droplet biogenesis in liver-derived cells. Together, our findings uncover a novel role for lysine methylation of PPARγ in the regulation of lipid synthesis and lipid droplet biogenesis, thereby identifying putative new therapeutic targets for lipid overproduction diseases, including metabolic dysfunction-associated fatty liver disease and obesity.