摘要
Human hepatocellular carcinoma(HCC)occurs almost exclusively in cirrhotic livers.Here,we report that hepatic loss of protein arginine methyltransferase 5(PRMT5)in mice is sufficient to cause cirrhosis and HCC in a clinically relevant way.Furthermore,pathological polyploidization induced by hepatic loss of PRMT5 promotes liver cirrhosis and hepatic tumorigenesis in aged liver.The loss of PRMT5 leads to hyperaccumulation of P21 and endoreplication-dependent formation of pathological mono-nuclear polyploid hepatocytes.PRMT5 and symmetric dimethylation at histone H4 arginine 3(H4R3me2s)directly associate with chromatin of P21 to suppress its transcription.More importantly,loss of P21 rescues the pathological mono-nuclear polyploidy and prevents PRMT5-deficiency-induced liver cirrhosis and HCC.Thus,our results indicate that PRMT5-mediated symmetric dimethylation at histone H4 arginine 3(H4R3me2s)is crucial for preventing pathological polyploidization,liver cirrhosis and tumorigenesis in mouse liver.
基金
financially supported by grants from the National Key R&D Program of China(2022YFC3600202,2018YFA0800902)
the National Natural Science Foundation of China(31730051,32170834).
