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,…
Peroxisome proliferator-activated receptor gamma (PPARγ) is a crucial transcriptional regulator responsible for adipogenesis and lipid storage in various cell types. Its regulation is vital for proper cell and organismal function. Dysregulation of PPARγ activity is associated with obesity, insulin resistance, and fatty liver disease.
Researchers have now discovered a new mechanism involving SETD6 binding to and methylation of PPARγ at lysine 170 (K170), both in vitro and in liver-derived cells. This methylation event is essential for PPARγ-mediated activation of SETD6 transcription via promoter binding, creating a positive feedback loop. RNA-sequencing analysis revealed that both SETD6 methylation and PPARγ K170 methylation are required for the full induction of lipid metabolism genes' expression, leading to lipid droplet biogenesis in liver-derived cells.
These findings highlight a novel role for lysine methylation of PPARγ in regulating lipid synthesis and lipid droplet biogenesis, suggesting potential new therapeutic targets for lipid overproduction diseases such as metabolic dysfunction-associated fatty liver disease and obesity.
Written by urgent.news from eLife's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
