Yin Yuxin’s research group discovered a new physiological function of the single-stranded DNA-binding protein RPA1 protein

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases characterized by the accumulation of excess lipids within liver cells. The pathophysiology of NAFLD has not yet been fully elucidated, and there is still a lack of effective treatment in the clinic. Therefore, in-depth study of the pathogenesis of NAFLD has become a research hotspot in the field of liver and metabolism.

On July 12, 2022, Yin Yuxin’s team from Peking University School of Basic Medicine published a research paper entitled “RPA1 Controls Chromatin Architecture and Maintains Lipid Metabolic Homeostasis” online in Cell Reports. By constructing mouse models, the paper found that the single-stranded DNA-binding protein RPA1 plays an important role in the development of fatty liver by using multiple omics methods such as pull-down, RNA-seq, ATAC-seq, and Cut&tag.

Yin Yuxin’s group first established an Rpa1 knockout mouse model (Cell Res. 2015.), mice observed to have heterozygous Rpa1 loss (Rpa1+/-) are more likely to induce colorectal cancer. The paper further found that Rpa1+/- mice are more susceptible to fatty liver disease, and that fatty liver phenotypes develop as they age or are induced by a high fat diet. In order to further study the role of RPA1 in the development of fatty liver disease, the research team newly constructed a mouse model of liver tissue-specific Rpa1 (Liver-Rpa1-KO) knockout, and found that Liver-Rpa1-KO mice develop fatty liver disease at four weeks of age and gradually progress to liver cancer, and 66.7% of Liver-Rpa1-KO mice progressed to liver cancer at 56 weeks of age. Through multi-omics methods such as Pull-down, RNA-seq, ATAC-seq, Cut&tag, and Seahorse and other experiments, it was found that RPA1 can regulate the chromatin accessibility of lipid metabolism-related genes by interacting with transcription factorSin HNF4A, chromatin remodeling factor FACT complex, etc., thereby regulating the transcription of lipid metabolism-related genes. Knockout Rpa1 causes the liver chromatin to be in a more dense state, inhibits the transcription of genes related to lipid metabolism, leads to a decrease in the rate of fatty acid β-oxidation in liver cells, the accumulation of fat, and the occurrence of fatty liver disease in mice. In addition, the expression level of RPA1 protein in liver samples of clinical fatty liver patients was found to be reduced by immunohistochemical staining of tissue chips, indicating that RPA1 plays an important role in clinical fatty liver generation.

In summary, the study confirms that RPA1 can regulate gene transcription by regulating chromatin conformation, discovers the important role of RPA1 protein in non-alcoholic fatty liver disease, further reveals the pathogenesis of non-alcoholic fatty liver disease from an epigenetic perspective, and provides new ideas for related disease prevention and innovative drug research and development.

Yin Qi, postdoctoral fellow of Peking University School of Medicine, Dr. Li Yang of the School of Basic Medicine, is the co-first author of the article, and Professor Yin Yuxin of the Institute of Systems Biomedicine of Peking University is the corresponding author. The work was strongly supported by Associate Professor Guo Limei of Peking University School of Basic Medical Sciences. The research was supported by the National Key R&D Program, the National Natural Science Foundation of China Key Project, the National Natural Science Foundation of China Youth Project, and the Peking University-Tsinghua Joint Center for Life Sciences. (Source: Science Network)

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