RPA1 controls chromatin architecture and maintains lipid metabolic homeostasis

Replication protein A1 (RPA1) is a single-stranded DNA binding protein that is known to participate in DNA replication, recombination and damage repair. However, little is known about RPA1’s role in controlling chromatin architecture and gene transcription. Further, physiological functions of RPA1 in mouse tissues still remain exclusive. Here we show that Rpa1 heterozygous mice developed age-depended fatty liver disease and are more susceptible to hepatic steatosis in response to high-fat diet. Liver specific deletion of Rpa1 impairs fatty acid oxidation, leading to hepatic steatosis and high incidence of hepatocellular carcinoma. Transcriptome analysis identified down-regulation of fatty acid oxidation related genes. Cleavage Under Targets and Tagmentation (CUT&Tag) and Assay for transposase-accessible chromatin using sequencing (ATAC-seq) revealed that RPA1 binds and regulates chromatin accessibility in regulatory regions of a group of genes involved in lipid metabolism in liver. Further, down-regulation of RPA1 was found in patients with fatty liver disease. Thus, our results not only established that RPA1 is critical controller of chromatin architecture and regulator of gene transcription, but also provided new insights into the epigenetic mechanism of fatty liver disease, which could inform future therapy. ATAC-seq on wild type (WT) and L-Rpa1-KO mice liver tissue. Liver mRNA profiles of wild type (WT) and L-Rpa1-KO mice. Examination of 3 different histone modifications, Pol II, HNF4A and RPA1 in mouse liver tissues.