Abstract
The extremely low efficiency of human embryonic stem cell (hESC) derivation using somatic cell nuclear transfer (SCNT) limits its potential application. Blastocyst formation from human SCNT embryos occurs at a low rate and with only some oocyte donors. We previously showed in mice that reduction of histone H3 lysine 9 trimethylation (H3K9me3) through ectopic expression of the H3K9me3 demethylase Kdm4d greatly improves SCNT embryo development. Here we show that overexpression of a related H3K9me3 demethylase KDM4A improves human SCNT, and that, as in mice, H3K9me3 in the human somatic cell genome is an SCNT reprogramming barrier. Overexpression of KDM4A significantly improves the blastocyst formation rate in human SCNT embryos by facilitating transcriptional reprogramming, allowing efficient derivation of SCNT-derived ESCs using adult Age-related Macular Degeneration (AMD) patient somatic nuclei donors. This conserved mechanistic insight has potential applications for improving SCNT in a variety of contexts, including regenerative medicine.
Highlights
The differentiated somatic cell genome can be reprogramed back into an embryonic state when the nucleus is exposed to the molecular milieu of the oocyte cytoplasm via somatic cell nuclear transfer (SCNT) (Gurdon, 1962), thereby enabling the generation of pluripotent embryonic stem cells (ESCs) from terminally differentiated somatic cells (Wakayama et al, 2001)
Through comparative transcriptomic and epigenomic analyses of mouse in vitro fertilization (IVF) and SCNT embryos, we have recently revealed that histone H3 lysine 9 trimethylation (H3K9me3) in the donor somatic cell genome functions as a barrier preventing transcriptional reprogramming by SCNT, leading to failure of zygotic genome activation (ZGA) and preimplantation development (Matoba et al, 2014)
We demonstrate that KDM4A overexpression significantly improves human SCNT embryo development, allowing efficient derivation of patientspecific NT-ESCs using oocytes obtained from donors whose oocytes failed to develop into blastocysts without the help of KDM4A overexpression
Summary
Young Gie Chung, Shogo Matoba, Yuting Liu, ..., Kwang Yul Cha, Dong Ryul Lee, Yi Zhang. Zhang and colleagues show that, as they found previously in mouse, injection of a histone demethylase improves the efficiency of human SCNT reprogramming. Using this approach they were able to reduce variability in success from different egg donors and derive human NT-ESC lines from patients with age-related macular degeneration.
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