Hepatocyte regeneration is driven by embryo-like DNA methylation reprogramming

As a result of partial hepatectomy (Phx), the remaining liver tissue undergoes a process of renewed proliferation that leads to rapid regeneration of the liver. By following the early stages of this process, we observed dramatic programmed changes in the DNA methylation profile, characterized by both de novo- and de- methylation events, with a subsequent return to the original adult pattern as the liver matures. Strikingly, these transient alterations partially mimic the DNA methylation state of embryonic hepatoblasts (E16.5), indicating that hepatocytes actually undergo epigenetic de-differentiation. Furthermore, Tet2/Tet3-deletion experiments demonstrated that these changes in methylation are necessary for carrying out basic embryonic functions, such as proliferation, a key step in liver regeneration. This implies that unlike tissue-specific regulatory regions that remain demethylated in the adult, early embryonic genes are programmed to first undergo de-methylation, followed by re-methylation as development proceeds. The discovery of this built-in system may open new targeting opportunities for regenerative medicine. Overall design: Methylation profiling by high throughput sequencing of control liver, 7 d after Phx, 2 m after Phx and of TET2/3 DKO liver 7d after Phx.