title: Histone Demethylase Expression Enhances Human Somatic Cell Nuclear Transfer Efficiency and Promotes Derivation of Pluripotent Stem Cells.
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.
authors.affiliation: Research Institute for Stem Cell Research, CHA Health Systems, Los Angeles, CA 90036, USA; CHA Stem Cell Institute, CHA University, Seoul 135-081, Korea.
authors.forename: Young Gie
authors.initials: YG
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: Shogo
authors.initials: S
authors.lastname: Matoba
authors.affiliation: 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.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Liu
authors.affiliation: CHA Stem Cell Institute, CHA University, Seoul 135-081, Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Eum
authors.affiliation: 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.
authors.forename: Falong
authors.initials: F
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: CHA Stem Cell Institute, CHA University, Seoul 135-081, Korea.
authors.forename: Jeoung Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Research Institute for Stem Cell Research, CHA Health Systems, Los Angeles, CA 90036, USA.
authors.forename: Vicken
authors.initials: V
authors.lastname: Sepilian
authors.affiliation: CHA Stem Cell Institute, CHA University, Seoul 135-081, Korea.
authors.forename: Kwang Yul
authors.initials: KY
authors.lastname: Cha
authors.affiliation: 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.
authors.forename: Dong Ryul
authors.initials: DR
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology; D002467:Cell Nucleus / Q000378:metabolism; D065150:Cellular Reprogramming; D054885:Cumulus Cells / Q000166:cytology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006570:Heterochromatin / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000737:chemistry; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D008268:Macular Degeneration / Q000378:metabolism; D051379:Mice; D053652:Nuclear Transfer Techniques; D009865:Oocytes / Q000166:cytology*; D039904:Pluripotent Stem Cells / Q000166:cytology*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D006570:Heterochromatin; D006657:Histones; D012333:RNA, Messenger; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D008239:Lysine
keywords: ESC derivation; H3K9me3; KDM4A; human; reprogramming barrier; somatic cell nuclear transfer