P53 mediated regulation of coactivator associated arginine methyltransferase 1 (CARM1) expression is critical for suppression of adipogenesis.

Abstract

Coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is a type I arginine methyltransferase that mediates transcriptional activation via methylation of histone H3 on R17, R26, and R42. CARM1 is also a coactivator of transcription of various transcription factors such as NF-kB, MEF2C, β-catenin, p53, PPAR-gamma etc. CARM1 has been functionally implicated in maintenance of pluripotency, cellular differentiation, and tumorigenesis; where its expression status plays an important role. Although its expression has been shown to be regulated by a few miRNAs in different contexts at post-transcriptional level, transcriptional regulation of CARM1 gene is still unexplored. In this report we demonstrate that CARM1 is a p53 responsive gene, where p53 could suppress CARM1 promoter-driven luciferase expression. CARM1 gene expression was found to be repressed by p53 in 3T3L1 preadipocytes when activated with Nutlin-3a treatment. Ectopic overexpression of CARM1 could rescue inhibitory effect of p53 on adipogenesis, suggesting a role of p53-CARM1 axis of regulation operational in the context of adipocyte differentiation. p53 and CARM1 showed antagonistic regulatory influence on PPAR-gamma expression; which suggests that p53-mediated suppression of adipogenesis could be partly via repression of CARM1 expression. Taken together these observations provide convincing mechanistic explanation for p53 function in the context of adipocyte differentiation process.