title: SUV4-20 activity in the preimplantation mouse embryo controls timely replication.
abstract: Extensive chromatin remodeling after fertilization is thought to take place to allow a new developmental program to start. This includes dynamic changes in histone methylation and, in particular, the remodeling of constitutive heterochromatic marks such as histone H4 Lys20 trimethylation (H4K20me3). While the essential function of H4K20me1 in preimplantation mouse embryos is well established, the role of the additional H4K20 methylation states through the action of the SUV4-20 methyltransferases has not been addressed. Here we show that Suv4-20h1/h2 are mostly absent in mouse embryos before implantation, underscoring a rapid decrease of H4K20me3 from the two-cell stage onward. We addressed the functional significance of this remodeling by introducing Suv4-20h1 and Suv4-20h2 in early embryos. Ectopic expression of Suv4-20h2 leads to sustained levels of H4K20me3, developmental arrest, and defects in S-phase progression. The developmental phenotype can be partially overcome through inhibition of the ATR pathway, suggesting that the main function for the remodeling of H4K20me3 after fertilization is to allow the timely and coordinated progression of replication. This is in contrast to the replication program in somatic cells, where H4K20me3 has been shown to promote replication origin licensing, and anticipates a different regulation of replication during this early developmental time window.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, U964, Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale (INSERM), F-67404 Illkirch, CU de Strasbourg, France.
authors.forename: André
authors.initials: A
authors.lastname: Eid
authors.affiliation: Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München, D-81377 München, Germany.
authors.forename: Diego
authors.initials: D
authors.lastname: Rodriguez-Terrones
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, U964, Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale (INSERM), F-67404 Illkirch, CU de Strasbourg, France.|Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München, D-81377 München, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Burton
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, U964, Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale (INSERM), F-67404 Illkirch, CU de Strasbourg, France.|Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München, D-81377 München, Germany.
authors.forename: Maria-Elena
authors.initials: ME
authors.lastname: Torres-Padilla
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001755:Blastocyst / Q000166:cytology / Q000201:enzymology*; D000066630:Ectopic Gene Expression; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D016678:Genome / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D015053:Zygote / Q000378:metabolism
chemical_list: D006657:Histones; D012333:RNA, Messenger; C570043:Suv4-20h protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: Suv4-20; heterochromatin; mouse embryo; replication stress