Histone Demethylase Expression Enhances Human Somatic Cell Nuclear Transfer Efficiency and Promotes Derivation of Pluripotent Stem Cells

Cell Stem Cell. 2015 Dec 3;17(6):758-766. doi: 10.1016/j.stem.2015.10.001. Epub 2015 Oct 29.


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.

Keywords: ESC derivation; H3K9me3; KDM4A; human; reprogramming barrier; somatic cell nuclear transfer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blastocyst / cytology
  • Cell Nucleus / metabolism
  • Cellular Reprogramming*
  • Cumulus Cells / cytology
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Heterochromatin / metabolism
  • Histone Demethylases / metabolism*
  • Histones / chemistry
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Lysine / chemistry
  • Macular Degeneration / metabolism
  • Mice
  • Nuclear Transfer Techniques
  • Oocytes / cytology*
  • Pluripotent Stem Cells / cytology*
  • RNA, Messenger / metabolism
  • Transcription, Genetic


  • Heterochromatin
  • Histones
  • RNA, Messenger
  • Histone Demethylases
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4A protein, human
  • Lysine

Associated data

  • GEO/GSE73362