RPA1 Remodels Liver Chromatin Architecture to Maintain Lipid Metabolic Homeostasis

Replication protein A(RPA), a ssDNA binding protein complex, participates in DNA replication, recombination and damage repair, but its physiological function remains elusive. Here, we show that heterozygous Rpa1 knockout mice were developmentally normal, but hypersensitive to ageing and high-fat-diet (HFD) induced hepatic steatosis. Liver specific deletion of Rpa1 leads to impaired lipid beta-oxidation, hepatic steatosis and subsequently hepatocellular carcinoma (HCC). Assays for RNA-seq, pull-down and transposase-accessible chromatin sequencing (ATAC-seq) reveal that RPA1 is required for transcription of a subgroup of lipid metabolic genes via altering chromatin accessibility landscape. Thus, our results suggest that RPA1 is a critical regulator of gene transcription and chromatin remodeling, linking a guardian of genome stability to lipid metabolic homeostasis.