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Epigenetic Marking Correlates with Developmental Potential in Cloned Bovine Preimplantation Embryos

2003; Elsevier BV; Volume: 13; Issue: 13 Linguagem: Inglês

10.1016/s0960-9822(03)00419-6

1879-0445

Fátima Santos, Valeri Zakhartchenko, Miodrag Stojković, Antoine H.F.M. Peters, Thomas Jenuwein, Eckhard Wolf, Wolf Reik, Wendy Dean,

Pluripotent Stem Cells Research

During differentiation, somatic nuclei acquire highly specialized DNA and chromatin modifications, which are thought to result in cellular memory of the differentiated state [1Bird A. DNA methylation patterns and epigenetic memory.Genes Dev. 2002; 16: 6-21Crossref PubMed Scopus (4995) Google Scholar]. Upon somatic nuclear transfer into oocytes, the donor nucleus may have to undergo reprogramming of these epigenetic marks in order to achieve totipotency. This may involve changes in epigenetic features similar to those that occur in normal embryos during early development [2Reik W. Dean W. Walter J. Epigenetic reprogramming in mammalian development.Science. 2001; 293: 1089-1093Crossref PubMed Scopus (2284) Google Scholar, 3Rideout 3rd, W.M. Eggan K. Jaenisch R. Nuclear cloning and epigenetic reprogramming of the genome.Science. 2001; 293: 1093-1098Crossref PubMed Scopus (613) Google Scholar, 4Kikyo N. Wolffe A.P. 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Genet. 2001; 28: 173-177Crossref PubMed Scopus (454) Google Scholar, 9Humpherys D. Eggan K. Akutsu H. Hochedlinger K. Rideout 3rd, W.M. Biniszkiewicz D. Yanagimachi R. Jaenisch R. Epigenetic instability in ES cells and cloned mice.Science. 2001; 293: 95-97Crossref PubMed Scopus (606) Google Scholar, 10Bourc'his D. Le Bourhis D. Patin D. Niveleau A. Comizzoli P. Renard J.P. Viegas-Pequignot E. Delayed and incomplete reprogramming of chromosome methylation patterns in bovine cloned embryos.Curr. Biol. 2001; 11: 1542-1546Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 11Inoue K. Kohda T. Lee J. Ogonuki N. Mochida K. Noguchi Y. Tanemura K. Kaneko-Ishino T. Ishino F. Ogura A. Faithful expression of imprinted genes in cloned mice.Science. 2002; 295: 297Crossref PubMed Scopus (234) Google Scholar, 12Kang Y.K. Park J.S. Koo D.B. Choi Y.H. Kim S.U. Lee K.K. Han Y.M. Limited demethylation leaves mosaic-type methylation states in cloned bovine pre-implantation embryos.EMBO J. 2002; 21: 1092-1100Crossref PubMed Scopus (185) Google Scholar]. Several reports reveal inefficient demethylation and inappropriate reestablishment of DNA methylation in quantitative and qualitative patterns on somatic nuclear transfer [7Dean W. Santos F. Stojkovic M. Zakhartchenko V. Walter J. Wolf E. Reik W. Conservation of methylation reprogramming in mammalian development aberrant reprogramming in cloned embryos.Proc. Natl. Acad. Sci. USA. 2001; 98: 13734-13738Crossref PubMed Scopus (814) Google Scholar, 8Kang Y.K. Koo D.B. Park J.S. Choi Y.H. Chung A.S. Lee K.K. Han Y.M. Aberrant methylation of donor genome in cloned bovine embryos.Nat. Genet. 2001; 28: 173-177Crossref PubMed Scopus (454) Google Scholar, 9Humpherys D. Eggan K. Akutsu H. Hochedlinger K. Rideout 3rd, W.M. Biniszkiewicz D. Yanagimachi R. Jaenisch R. Epigenetic instability in ES cells and cloned mice.Science. 2001; 293: 95-97Crossref PubMed Scopus (606) Google Scholar, 10Bourc'his D. Le Bourhis D. Patin D. Niveleau A. Comizzoli P. Renard J.P. Viegas-Pequignot E. Delayed and incomplete reprogramming of chromosome methylation patterns in bovine cloned embryos.Curr. Biol. 2001; 11: 1542-1546Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 11Inoue K. Kohda T. Lee J. Ogonuki N. Mochida K. Noguchi Y. Tanemura K. Kaneko-Ishino T. Ishino F. Ogura A. Faithful expression of imprinted genes in cloned mice.Science. 2002; 295: 297Crossref PubMed Scopus (234) Google Scholar, 12Kang Y.K. Park J.S. Koo D.B. Choi Y.H. Kim S.U. Lee K.K. Han Y.M. Limited demethylation leaves mosaic-type methylation states in cloned bovine pre-implantation embryos.EMBO J. 2002; 21: 1092-1100Crossref PubMed Scopus (185) Google Scholar]. Here we examine histone H3 lysine 9 (H3-K9) methylation and acetylation in normal embryos and in those created by somatic nuclear transfer. We find that H3-K9 methylation is reprogrammed in parallel with DNA methylation in normal embryos. However, the majority of cloned embryos exhibit H3-K9 hypermethylation associated with DNA hypermethylation, suggesting a genome-wide failure of reprogramming. Strikingly, the precise epigenotype in cloned embryos depends on the donor cell type, and the proportion of embryos with normal epigenotypes correlates closely with the proportion developing to the blastocyst stage. These results suggest a mechanistic link between DNA and histone methylation in the mammalian embryo and reveal an association between epigenetic marks and developmental potential of cloned embryos.