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H3K4 Methylation-Dependent Memory of Somatic Cell Identity Inhibits Reprogramming and Development of Nuclear Transfer Embryos

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Hörmanseder, E 
Simeone, A 
Allen, GE 
Bradshaw, CR 
Figlmüller, M 


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.



nuclear transfer, reprogramming, epigenetic memory, H3K4me3, Kdm5b, endoderm, cell-fate stability

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Cell Stem Cell

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Elsevier (Cell Press)
Medical Research Council (MR/P000479/1)
Wellcome Trust (092096/Z/10/Z)
Medical Research Council (G1001690)
Medical Research Council (MR/K011022/1)
Wellcome Trust (101050/Z/13/Z)
Cancer Research Uk (None)
This work was funded by the Molecular Research Council ( MR/P000479/1 ), the Wellcome Trust ( 101050/Z/13/Z and 092096/Z/10/Z ), and Cancer Research UK ( C6946/A14492 ). E.H. was a recipient of a long-term fellowship from the European Molecular Biology Organization (EMBO) and Isaac Newton Trust funding.