title: H3K4 Methylation-Dependent Memory of Somatic Cell Identity Inhibits Reprogramming and Development of Nuclear Transfer Embryos.
abstract: Vertebrate eggs can induce the nuclear reprogramming of somatic cells to enable production of cloned animals. Nuclear reprogramming is relatively inefficient, and the development of the resultant embryos is frequently compromised, in part due to the inappropriate expression of genes previously active in the donor nucleus. Here, we identify H3K4 methylation as a major epigenetic roadblock that limits transcriptional reprogramming and efficient nuclear transfer (NT). Widespread expression of donor-cell-specific genes was observed in inappropriate cell types in NT embryos, limiting their developmental capacity. The expression of these genes in reprogrammed embryos arises from epigenetic memories of a previously active transcriptional state in donor cells that is characterized by high H3K4 methylation. Reducing H3K4 methylation had little effect on gene expression in donor cells, but it substantially improved transcriptional reprogramming and development of NT embryos. These results show that H3K4 methylation imposes a barrier to efficient nuclear reprogramming and suggest approaches for improving reprogramming strategies.
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK. Electronic address: e.hoermanseder@gurdon.cam.ac.uk.
authors.forename: Eva
authors.initials: E
authors.lastname: Hörmanseder
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Simeone
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: George E
authors.initials: GE
authors.lastname: Allen
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Bradshaw
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Figlmüller
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Department of Zoology, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: John
authors.initials: J
authors.lastname: Gurdon
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK. Electronic address: j.jullien@gurdon.cam.ac.uk.
authors.forename: Jerome
authors.initials: J
authors.lastname: Jullien
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D053652:Nuclear Transfer Techniques; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D006657:Histones; D029867:Xenopus Proteins
keywords: H3K4me3; Kdm5b; cell-fate stability; endoderm; epigenetic memory; nuclear transfer; reprogramming