Ablation of PRMT6 reveals a role as a negative transcriptional regulator of the p53 tumor suppressor

Abstract

Arginine methylation of histones is a well-known regulator of gene expression. Protein arginine methyltransferase 6 (PRMT6) has been shown to function as a transcriptional repressor by methylating the histone H3 arginine 2 [H3R2(me2a)] repressive mark; however, few targets are known. To define the physiological role of PRMT6 and to identify its targets, we generated PRMT6−/− mouse embryo fibroblasts (MEFs). We observed that early passage PRMT6−/− MEFs had growth defects and exhibited the hallmarks of cellular senescence. PRMT6−/− MEFs displayed high transcriptional levels of p53 and its targets, p21 and PML. Generation of PRMT6−/−; p53−/− MEFs prevented the premature senescence, suggesting that the induction of senescence is p53-dependent. Using chromatin immunoprecipitation assays, we observed an enrichment of PRMT6 and H3R2(me2a) within the upstream region of Trp53. The PRMT6 association and the H3R2(me2a) mark were lost in PRMT6−/− MEFs and an increase in the H3K4(me3) activator mark was observed. Our findings define a new regulator of p53 transcriptional regulation and define a role for PRMT6 and arginine methylation in cellular senescence.

Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene

“…These functions agree with the nuclear localization of Prmt6 (25). To date, many target genes of Prmt6 have been reported, including HoxA2 (17), thrombospondin-1 (26), p21 (20), p27 (27), p53 (21), Oct4 and Nanog (28), CD41 (29), and IL-6 (24).…”

Deregulated expression of selected histone methylases and demethylases in prostate carcinoma

“…The overexpression of this histone modifier, already reported in bladder and lung cancer, might lead to a decrease in p53 levels, fostering tumorigenesis (Yoshimatsu et al 2011, Neault et al 2012. Interestingly, PRMT6 proved to be the HMT that best discriminated PCa from NPTs, further supporting a role for its deregulation in prostate carcinogenesis.…”

Exchange Factor TBL1 and Arginine Methyltransferase PRMT6 Cooperate in Protecting G Protein Pathway Suppressor 2 (GPS2) from Proteasomal Degradation

“…in other cellular compartments or in a tissue-specific manner (33), our data suggest that PRMT6 is the main enzyme regulating GPS2 methylation and stability in the nucleus. Intriguingly, PRMT6 has been implicated in many processes related to GPS2 functions, including chromatin remodeling, cell cycle regulation, p53 activity, and transcriptional regulation by the NF-B pathway (45)(46)(47)(48), suggesting, as in the case of TBL1, that some of the effects observed when modulating PRMT6 levels may be attributed to changes in GPS2-mediated functions.…”