PRMT5 determines the pattern of polyploidization and prevents liver from cirrhosis and carcinogenesis

Jincheng Wang; Xiang Huang; Daoshan Zheng; Qiuling Li; Mei Mei; Shilai Bao

doi:10.1016/j.jgg.2022.04.008

Volume 50 Issue 2

Feb. 2023

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PRMT5 determines the pattern of polyploidization and prevents liver from cirrhosis and carcinogenesis

doi: 10.1016/j.jgg.2022.04.008

a. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;
b. School of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China

Funds:

D Program of China (2022YFC3600202, 2018YFA0800902), and the National Natural Science Foundation of China (31730051, 32170834).

This work was financially supported by grants from the National Key R&

Received Date: 2022-03-27
Accepted Date: 2022-04-12
Rev Recd Date: 2022-04-12
Publish Date: 2022-04-30

Abstract

Abstract

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 hyper-accumulation 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.
- Pathological polyploidizaion,
- Hepatocellular carcinoma,
- Cirrhosis,
- PRMT5,
- Aging

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References(54)

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