PMID- 25417163 OWN - NLM STAT- MEDLINE DCOM- 20150317 LR - 20220409 IS - 1097-4172 (Electronic) IS - 0092-8674 (Print) IS - 0092-8674 (Linking) VI - 159 IP - 4 DP - 2014 Nov 6 TI - Embryonic development following somatic cell nuclear transfer impeded by persisting histone methylation. PG - 884-95 LID - S0092-8674(14)01243-4 [pii] LID - 10.1016/j.cell.2014.09.055 [doi] AB - Mammalian oocytes can reprogram somatic cells into a totipotent state enabling animal cloning through somatic cell nuclear transfer (SCNT). However, the majority of SCNT embryos fail to develop to term due to undefined reprogramming defects. Here, we identify histone H3 lysine 9 trimethylation (H3K9me3) of donor cell genome as a major barrier for efficient reprogramming by SCNT. Comparative transcriptome analysis identified reprogramming resistant regions (RRRs) that are expressed normally at 2-cell mouse embryos generated by in vitro fertilization (IVF) but not SCNT. RRRs are enriched for H3K9me3 in donor somatic cells and its removal by ectopically expressed H3K9me3 demethylase Kdm4d not only reactivates the majority of RRRs, but also greatly improves SCNT efficiency. Furthermore, use of donor somatic nuclei depleted of H3K9 methyltransferases markedly improves SCNT efficiency. Our study thus identifies H3K9me3 as a critical epigenetic barrier in SCNT-mediated reprogramming and provides a promising approach for improving mammalian cloning efficiency. FAU - Matoba, Shogo AU - Matoba S AD - Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA. FAU - Liu, Yuting AU - Liu Y AD - Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA. FAU - Lu, Falong AU - Lu F AD - Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA. FAU - Iwabuchi, Kumiko A AU - Iwabuchi KA AD - Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA. FAU - Shen, Li AU - Shen L AD - Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA. FAU - Inoue, Azusa AU - Inoue A AD - Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA. FAU - Zhang, Yi AU - Zhang Y AD - Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: yzhang@genetics.med.harvard.edu. LA - eng SI - GEO/GSE59073 GR - U01 DK089565/DK/NIDDK NIH HHS/United States GR - U01DK089565/DK/NIDDK NIH HHS/United States GR - Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141030 PL - United States TA - Cell JT - Cell JID - 0413066 RN - 0 (Histones) RN - 0 (Repressor Proteins) RN - EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases) RN - EC 1.14.11.- (KDM4D protein, mouse) RN - EC 2.1.1. (Suv39h1 protein, mouse) RN - EC 2.1.1.- (Methyltransferases) SB - IM MH - Animals MH - Cloning, Organism/methods MH - Embryo, Mammalian/metabolism MH - *Embryonic Development MH - Female MH - *Histone Code MH - Histones/*metabolism MH - Jumonji Domain-Containing Histone Demethylases/metabolism MH - Male MH - Methylation MH - Methyltransferases/metabolism MH - Mice, Inbred C57BL MH - Mice, Inbred DBA MH - *Nuclear Transfer Techniques MH - Repressor Proteins/metabolism MH - Zygote PMC - PMC4243038 MID - NIHMS634073 EDAT- 2014/11/25 06:00 MHDA- 2015/03/18 06:00 PMCR- 2015/11/06 CRDT- 2014/11/24 06:00 PHST- 2014/07/01 00:00 [received] PHST- 2014/09/01 00:00 [revised] PHST- 2014/09/19 00:00 [accepted] PHST- 2014/11/24 06:00 [entrez] PHST- 2014/11/25 06:00 [pubmed] PHST- 2015/03/18 06:00 [medline] PHST- 2015/11/06 00:00 [pmc-release] AID - S0092-8674(14)01243-4 [pii] AID - 10.1016/j.cell.2014.09.055 [doi] PST - ppublish SO - Cell. 2014 Nov 6;159(4):884-95. doi: 10.1016/j.cell.2014.09.055. Epub 2014 Oct 30.