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

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) 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, PPAR{gamma}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 PPAR{gamma} at lysine 170 (K170) both in vitro and in liver-derived cells. This methylation event, in turn, is required for PPAR{gamma}-mediated activation of SETD6 transcription via promoter binding, forming a positive feedback regulatory loop. RNA sequencing revealed that both SETD6 and PPAR{gamma} 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 PPAR{gamma} in the regulation of lipid synthesis and lipid droplet biogenesis, thereby identifying putative new therapeutic targets for lipid over-production diseases, including MAFLD (Metabolic dysfunction-associated fatty liver disease) and obesity.