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bioRxiv · 10.64898/2026.04.10.717761

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

Nashnaz, N.·Goldberg, D.·Abramov, M.·Chopra, A.·Muallem, H.·Haim, Y.·Feldman, M.·Rudich, A.·Levy, D.
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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.

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Nashnaz, N., Goldberg, D., Abramov, M., Chopra, A., Muallem, H., Haim, Y., Feldman, M., Rudich, A., Levy, D.. 2026-04-13. SETD6-mediated methylation of PPARγ establishes a transcriptional feedback circuit promoting lipid accumulation in liver-derived cells. https://doi.org/10.64898/2026.04.10.717761

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