Cell sub-issue: Yin Yuxin's team 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 excessive lipid accumulation in hepatocytes
.
The pathophysiological mechanism of NAFLD has not been fully elucidated, and there is still no effective treatment in clinical practice
.
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, a research paper titled "RPA1 Controls Chromatin Architecture and Maintains Lipid Metabolic Homeostasis" was published online by the team of Yin Yuxin from Peking University-Tsinghua Life Science Joint Center and Peking University School of Basic Medicine in the journal "Cell Reports"
.
In this paper, by constructing a mouse model and applying multi-omics methods such as pull-down, RNA-seq, ATAC-seq and Cut&tag, it was found that the single-stranded DNA-binding protein RPA1 plays an important role in the occurrence and development of fatty liver
.

Yin Yuxin's research group first established an Rpa1 knockout mouse model in 2015 (Cell Res.
2015.
), and observed that mice with heterozygous loss of Rpa1 (Rpa1+/-) were more likely to induce colorectal cancer
.
The paper further found that Rpa1+/- mice were more susceptible to fatty liver and developed a fatty liver phenotype with age or induction of a high fat diet
.
In order to further study the role of RPA1 in the occurrence and development of fatty liver, the research group newly constructed a liver tissue-specific Rpa1 (Liver-Rpa1-KO) knockout mouse model and found that Liver-Rpa1-KO mice suffered from fat at four weeks of age.
Liver and progressively progressed to liver cancer, with 66.
7% of Liver-Rpa1-KO mice progressing to liver cancer at 56 weeks of age
.
Through multi-omics methods such as Pull-down, RNA-seq, ATAC-seq, Cut&tag, and experiments such as Seahorse, it was found that RPA1 can regulate lipid metabolism by interacting with transcription factor HNF4A, chromatin remodeling factor FACT complex, etc.
Chromatin accessibility of related genes, thereby regulating the transcription of lipid metabolism-related genes
.
Knockout of Rpa1 resulted in a more compact state of hepatic chromatin and inhibited the transcription of lipid metabolism-related genes, resulting in a decrease in the rate of fatty acid β-oxidation in hepatocytes, accumulation of fat, and the occurrence of fatty liver in mice
.
In addition, the expression level of RPA1 protein in the liver samples of clinical fatty liver patients was found to be reduced by tissue microarray immunohistochemical staining, indicating that RPA1 plays an important role in the occurrence of clinical fatty liver
.

In conclusion, this study confirmed that RPA1 can regulate gene transcription by regulating chromatin conformation, discovered the important role of RPA1 protein in non-alcoholic fatty liver disease, and further revealed non-alcoholic fatty liver disease from an epigenetic perspective.
The pathogenesis of liver disease provides new ideas for the prevention of related diseases and the development of innovative drugs
.