Hepatocyte regeneration is driven by embryo-like DNA methylation reprogramming

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 n...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2024-04, Vol.121 (16), p.e2314885121
Main Authors: Falick Michaeli, Tal, Sabag, Ofra, Azria, Batia, Fok, Rimma, Abudi, Nathalie, Abramovitch, Rinat, Monin, Jonathan, Gielchinsky, Yuval, Cedar, Howard, Bergman, Yehudit
Format: Article
Language:English
Subjects:
Biological Sciences
Demethylation
Deoxyribonucleic acid
DNA
DNA Methylation
Embryo, Mammalian - metabolism
Embryos
Epigenetics
Hepatectomy
Hepatocytes
Liver
Regeneration (physiology)
Regenerative medicine
Regulatory sequences
Tissue engineering
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Summary: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.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2314885121