GADD45 promotes locus-specific DNA demethylation and 2C cycling in embryonic stem cells.

Autor:	Schüle KM; Institute of Molecular Biology (IMB), 55128 Mainz, Germany., Leichsenring M; Institute of Molecular Biology (IMB), 55128 Mainz, Germany., Andreani T; Institute of Molecular Biology (IMB), 55128 Mainz, Germany., Vastolo V; Institute of Molecular Biology (IMB), 55128 Mainz, Germany., Mallick M; Institute of Molecular Biology (IMB), 55128 Mainz, Germany., Musheev MU; Institute of Molecular Biology (IMB), 55128 Mainz, Germany., Karaulanov E; Institute of Molecular Biology (IMB), 55128 Mainz, Germany., Niehrs C; Institute of Molecular Biology (IMB), 55128 Mainz, Germany.; German Cancer Research Center (DKFZ), Division of Molecular Embryology, 69120 Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	Genes & development [Genes Dev] 2019 Jul 01; Vol. 33 (13-14), pp. 782-798. Date of Electronic Publication: 2019 Jun 06.
DOI:	10.1101/gad.325696.119
Abstrakt:	Mouse embryonic stem cell (ESC) cultures contain a rare cell population of "2C-like" cells resembling two-cell embryos, the key stage of zygotic genome activation (ZGA). Little is known about positive regulators of the 2C-like state and two-cell stage embryos. Here we show that GADD45 (growth arrest and DNA damage 45) proteins, regulators of TET (TET methylcytosine dioxygenase)-mediated DNA demethylation, promote both states. Methylome analysis of Gadd45a , b , g triple-knockout (TKO) ESCs reveal locus-specific DNA hypermethylation of ∼7000 sites, which are enriched for enhancers and loci undergoing TET-TDG (thymine DNA glycosylase)-mediated demethylation. Gene expression is misregulated in TKOs, notably upon differentiation, and displays signatures of DNMT (DNA methyltransferase) and TET targets. TKOs manifest impaired transition into the 2C-like state and exhibit DNA hypermethylation and down-regulation of 2C-like state-specific genes. Gadd45a , b double-mutant mouse embryos display embryonic sublethality, deregulated ZGA gene expression, and developmental arrest. Our study reveals an unexpected role of GADD45 proteins in embryonic two-cell stage regulation. (© 2019 Schüle et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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