Recruitment of MEP50/PRMT5 in Epigenetic Modifications for Lipogenesis in Fasting

USF-1 is the molecular switch regulating lipogenesis at the transcriptional level upon nutritional changes and insulin stimuli. We have previously reported that DNA-PK mediates USF-1 S262 phosphorylation and K237 acetylation, which function as molecular switches to control the recruitment of different classes of protein complexes including HAT/HDAC, lipoBAF in transcriptional activation/repression of lipogenic genes. In searching for interacting proteins that are USF-1 S262 phosphorylation specific, we found that MEP50/PRMT5 protein complex could interact with non-phosphorylated USF-1 upon starvation. Recruitment of MEP50/PRMT5 on lipogenic gene promoters brought a repressive histone mark H4R3 methylation, resulting in transcriptional repression of lipogenesis. Our results also showed that MEP50/PRMT5 mediates USF-1 arginine methylation at R214 site upon starvation. Knocking down MEP50 abolishedboth H4R3 and USF-1 R214 methylation. As in vivo, mice upon fasting showed similar observations as those in hepatocytes upon starvation, suggesting MEP50/PRMT5-mediated H4R3 and USF-1 methylation could be of physiological significance. While dynamic histone acetylation and associated HATs have been studied for decade for epigenetic regulation of lipogenesis, here we first reported that histone methylation and associated epigenetic modifiers also play a role in this regulation in response to feeding/insulin. Together, our results providedthe molecular link from DNA-PK insulin signalling and USF phosphorylation to epigenetic regulation of lipogenesis. Furthermore, our work not only identified a novel functional USF-1 methylation to be critical to lipogenic gene transcription but also demonstrated one of the few examples which arginine methylation occurs on non-histone proteins.