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

Young Gie Chung; Shogo Matoba; Yuting Liu; Jin Hee Eum; Falong Lu; Wei Jiang; Jeoung Eun Lee; Vicken Sepilian; Kwang Yul Cha; Dong Ryul Lee; Yi Zhang

doi:10.1016/j.stem.2015.10.001

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.

Authors

Affiliations

¹ Research Institute for Stem Cell Research, CHA Health Systems, Los Angeles, CA 90036, USA; CHA Stem Cell Institute, CHA University, Seoul 135-081, Korea.
² Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
³ CHA Stem Cell Institute, CHA University, Seoul 135-081, Korea.
⁴ Research Institute for Stem Cell Research, CHA Health Systems, Los Angeles, CA 90036, USA.
⁵ Research Institute for Stem Cell Research, CHA Health Systems, Los Angeles, CA 90036, USA; CHA Stem Cell Institute, CHA University, Seoul 135-081, Korea. Electronic address: drleedr@cha.ac.kr.
⁶ Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: yzhang@genetics.med.harvard.edu.

PMID: 26526725
DOI: 10.1016/j.stem.2015.10.001

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.

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

Substances

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

Associated data

GEO/GSE73362

Grants and funding

Howard Hughes Medical Institute/United States