Reviewer #2 (Public review): SETD6-mediated methylation of PPARγ establishes a transcriptional feedback circuit promoting lipid accumulation in liver-derived cells

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Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation in hepatocytes and affects approximately 25% of the global population. The nuclear receptor PPARγ is a central regulator of lipid storage and metabolic gene expression in the liver; however, how post-translational modifications modulate its transcriptional activity remains incompletely understood. Here, we identify lysine methylation as a regulatory mechanism controlling PPARγ function. We show that the lysine methyltransferase SETD6 directly binds to and mono-methylates PPARγ at lysine 170 within its DNA-binding domain. This modification enhances PPARγ occupancy at target gene promoters and promotes the expression of lipid metabolism genes.Mechanistically, SETD6-mediated methylation of PPARγ facilitates its recruitment to chromatin and is required for full transcriptional activation of key lipid droplet-associated genes, including MOGAT1 and PLIN2. In turn, PPARγ directly activates SETD6 transcription in a methylation-dependent manner, establishing a positive feedback circuit that amplifies lipid metabolic gene expression. Transcriptomic analysis reveals that both SETD6 and PPARγ K170 methylation regulate overlapping gene networks enriched for lipid metabolism pathways. Functionally, disruption of SETD6 or mutation of PPARγ at K170 impairs lipid droplet accumulation in hepatocytes.Together, our findings uncover a previously unrecognized post-translational modification of PPARγ that regulates its chromatin binding and transcriptional activity, and define a SETD6–PPARγ regulatory axis that promotes hepatic lipid accumulation. These results provide new insight into epigenetic control of metabolic gene expression and suggest potential therapeutic targets for NAFLD.

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