Protein arginine methyltransferase PRMT1 promotes adipogenesis by modulating transcription factors C/EBPβ and PPARγ

Protein arginine methyltransferase 1 (PRMT1) methylates a variety of histone and nonhistone protein substrates to regulate multiple cellular functions such as transcription, DNA damage response, and signal transduction. It has been reported as an emerging regulator of various metabolic pathways including glucose metabolism in the liver, atrophy in the skeletal muscle, and lipid catabolism in the adipose tissue. However, the underlying mechanisms governing how PRMT1 regulates adipogenesis remain elusive. Here, we delineate the roles of PRMT1 in mitotic clonal expansion and adipocyte differentiation. Gain and loss of functions demonstrate that PRMT1 is essential for adipogenesis of 3T3-L1 and C3H10T1/2 cells. Mechanistically, we show PRMT1 promotes the expression of transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) by catalyzing histone modification H4R3me2a and impedes the activation of Wnt/β-catenin signaling by increasing the level of Axin to accelerate adipogenic differentiation. In addition, we demonstrate mitotic clonal expansion is suppressed by PRMT1 deficiency. PRMT1 interacts with transcription factor CCATT enhancer-binding protein β (C/EBPβ), and the absence of PRMT1 leads to the depressed phosphorylation of C/EBPβ. Interestingly, we discover PRMT1 acts as a positive regulator of C/EBPβ protein stability through decreasing the level of E3 ubiquitin ligase Smurf2, which promotes the ubiquitination and degradation of C/EBPβ, thus facilitating adipogenesis. Collectively, these discoveries highlight a critical role of PRMT1 in adipogenesis and provide potential therapeutic targets for the treatment of obesity.