TY  - JOUR
AU  - Falick Michaeli, Tal
AU  - Sabag, Ofra
AU  - Azria, Batia
AU  - Fok, Rimma
AU  - Abudi, Nathalie
AU  - Abramovitch, Rinat
AU  - Monin, Jonathan
AU  - Gielchinsky, Yuval
AU  - Cedar, Howard
AU  - Bergman, Yehudit
TI  - Hepatocyte regeneration is driven by embryo-like DNA methylation reprogramming.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 121
IS  - 16
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DKFZ-2025-02495
SP  - e2314885121
PY  - 2024
N1  - #DKFZ-MOST-Ca200#
AB  - 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.
KW  - DNA Methylation
KW  - Embryo, Mammalian: metabolism
KW  - Hepatocytes
KW  - DNA methylation (Other)
KW  - dedifferentiation (Other)
KW  - partial hepatectomy (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:38588413
C2  - pmc:PMC11032470
DO  - DOI:10.1073/pnas.2314885121
UR  - https://inrepo02.dkfz.de/record/306269
ER  -