Hepatocyte regeneration is driven by embryo-like DNA methylation reprogramming

Tal Falick Michaeli, Ofra Sabag, Batia Azria, Rimma Fok, Nathalie Abudi, Rinat Abramovitch, Jonathan Monin, Yuval Gielchinsky, Howard Cedar, Yehudit Bergman

Research output: Contribution to journalArticlepeer-review

Abstract

As a result of partial hepatectomy, 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 demethylation 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 dedifferentiation. 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 demethylation, followed by remethylation as development proceeds. The identification of this built-in system may open targeting opportunities for regenerative medicine.

Original languageAmerican English
Pages (from-to)e2314885121
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number16
DOIs
StatePublished - 16 Apr 2024

Keywords

  • DNA methylation
  • dedifferentiation
  • partial hepatectomy

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