DNA methylation maintenance at the p53 locus initiates biliary-mediated liver regeneration

In cases of extensive liver injury, biliary epithelial cells (BECs) dedifferentiate into bipotential progenitor cells (BPPCs), then redifferentiate into hepatocytes and BECs to accomplish liver regeneration. Whether epigenetic regulations, particularly DNA methylation maintenance enzymes, play a role in this biliary-mediated liver regeneration remains unknown. Here we show that in response to extensive hepatocyte damages, expression of dnmt1 is upregulated in BECs to methylate DNA at the p53 locus, which represses p53 transcription, and in turn, derepresses mTORC1 signaling to activate BEC dedifferentiation. After BEC dedifferentiation and BPPC formation, DNA methylation at the p53 locus maintains in BPPCs to continue blocking p53 transcription, which derepresses Bmp signaling to induce BPPC redifferentiation. Thus, this study reveals promotive roles and mechanisms of DNA methylation at the p53 locus in both dedifferentiation and redifferentiation stages of biliary-mediated liver regeneration, implicating DNA methylation and p53 as potential targets to stimulate regeneration after extensive liver injury.