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

Publication date: Available online 30 March 2017
Source:Cell Stem Cell
Author(s): Eva Hörmanseder, Angela Simeone, George E. Allen, Charles R. Bradshaw, Magdalena Figlmüller, John Gurdon, Jerome Jullien
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.

Graphical abstract

Teaser

Hörmanseder et al. find that persistent memories of transcriptional activity in donor cell identity genes present a barrier to cell-fate reprogramming following nuclear transfer. They show that reducing H3K4 methylation in donor cells reduces transcriptional memory and improves the development of embryos derived by nuclear transfer.


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