Human pluripotent stem cells hold potential for regenerative medicine, but available cell types have significant limitations. Although embryonic stem cells (ES cells) from in vitro fertilized embryos (IVF ES cells) represent the ‘gold standard’, they are allogeneic to patients. Autologous induced pluripotent stem cells (iPS cells) are prone to epigenetic and transcriptional aberrations. To determine whether such abnormalities are intrinsic to somatic cell reprogramming or secondary to the reprogramming method, genetically matched sets of human IVF ES cells, iPS cells and nuclear transfer ES cells (NT ES cells) derived by somatic cell nuclear transfer (SCNT) were subjected to genome-wide analyses. Both NT ES cells and iPS cells derived from the same somatic cells contained comparable numbers of de novo copy number variations. In contrast, DNA methylation and transcriptome profiles of NT ES cells corresponded closely to those of IVF ES cells, whereas iPS cells differed and retained residual DNA methylation patterns typical of parental somatic cells. Thus, human somatic cells can be faithfully reprogrammed to pluripotency by SCNT and are therefore ideal for cell replacement therapies.

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Gene Expression Omnibus

Data deposits

Processed data sets can be downloaded from the NCBI GEO under accession GSE53096 for RNA-seq, SNP array and 450K methylation array, and accession GSE57179 for MethylC-seq data. Analysed MethylC-seq data sets can also be accessed at http://neomorph.salk.edu/SCNT/browser.html.


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The authors acknowledge the OHSU Embryonic Stem Cell Research Oversight Committee and the Institutional Review Board for providing oversight and guidance. We thank oocyte and sperm donors and the Women’s Health Research Unit staff at the Center for Women’s Health, University Fertility Consultants and the Reproductive Endocrinology and Infertility Division in the Department of Obstetrics and Gynecology of Oregon Health and Science University for their support and procurement of human gametes. We are grateful to C. Penedo for microsatellite analysis and W. Sanger and D. Zaleski for karyotyping services. We are also indebted to Y. Li, H. Sritanaudomchai and D. Melguizo Sanchis for their technical support. We thank the staff at the Institute for Genomic Medicine Genomics Facility at UCSD for running the Infinium HumanMethylation450 BeadChips and sequencing of the RNA-seq libraries. The authors acknowledge the Texas Advanced Computing Center (TACC) at The University of Texas at Austin (http://www.tacc.utexas.edu) and the San Diego Supercomputing Center (through an allocation from the eXtreme Science and Engineering Discovery Environment (XSEDE)) for providing HPC resources that have contributed to the research results reported within this paper. SCNT and iPS cell studies were supported by grants from the Leducq Foundation and OHSU institutional funds. R.M., K.S., R.T. and L.C.L. were supported by the UCSD Department of Reproductive Medicine. Methylome studies were supported by the Salk International Council Chair fund endowment and the Mary K. Chapman Foundation to J.R.E. J.R.E. is an investigator of the Howard Hughes Medical Institute and the Gordon and Betty Moore Foundation (GMBF3034). A.P. received a fellowship from the Swedish Research Council, Vetenskapsrådet. E.K. was partially funded by a fellowship from the Collins Medical Trust.

Author information

Author notes

    • Hong Ma
    •  & Robert Morey

    These authors contributed equally to this work.

    • Masahito Tachibana
    •  & Alim Polat

    Present addresses: Department of Obstetrics and Gynecology, South Miyagi Medical Center, Shibata-gun, Miyagi 989-1253, Japan (M.T.); Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden (A.P.).


  1. Center for Embryonic Cell and Gene Therapy, Oregon Health & Science University, 3303 Southwest Bond Avenue, Portland, Oregon 97239, USA

    • Hong Ma
    • , Brittany Daughtry
    • , Eunju Kang
    • , Rebecca Tippner-Hedges
    • , Riffat Ahmed
    • , Nuria Marti Gutierrez
    • , Crystal Van Dyken
    •  & Shoukhrat Mitalipov
  2. Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA

    • Hong Ma
    • , Brittany Daughtry
    • , Masahito Tachibana
    • , Eunju Kang
    • , Rebecca Tippner-Hedges
    • , Riffat Ahmed
    • , Nuria Marti Gutierrez
    • , Crystal Van Dyken
    • , Alim Polat
    • , Atsushi Sugawara
    • , Michelle Sparman
    • , Don P.Wolf
    •  & Shoukhrat Mitalipov
  3. Department of Reproductive Medicine, University of California, San Diego, Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, USA

    • Robert Morey
    • , Karen Sabatini
    • , Rathi D. Thiagarajan
    •  & Louise C. Laurent
  4. Genomic Analysis Laboratory, the Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Ryan C. O'Neil
    • , Yupeng He
    • , Matthew D. Schultz
    • , Manoj Hariharan
    • , Joseph R. Nery
    • , Rosa Castanon
    •  & Joseph R. Ecker
  5. Bioinformatics Program, University of California at San Diego, La Jolla, California 92093, USA

    • Ryan C. O'Neil
    •  & Yupeng He
  6. University Pathologists LLC, Boston University School of Medicine, Roger Williams Medical Center, Providence, Rhode Island 02118, USA

    • Sumita Gokhale
  7. Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA

    • Paula Amato
    •  & Shoukhrat Mitalipov
  8. Howard Hughes Medical Institute, the Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Joseph R. Ecker


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H.M., R.M., L.C.L. and S.M. conceived the study and designed the experiments. P.A., M.S. and N.M.G. coordinated recruitment of gamete donors. P.A. performed ovarian stimulations and oocyte retrievals. M.T., M.S., N.M.G. and S.M. conducted SCNT, IVF and embryo culture experiments. R.T.-H., S.M., M.T., M.S., N.M.G., H.M., A.P., B.D., E.K., A.S. and R.A. derived and cultured IVF ES cells, NT ES cells and iPS cells. S.G. performed teratoma analysis. H.M., M.T. and C.V.D. performed the DNA and RNA extractions, mtDNA amplification refractory mutation system qPCR analyses, and qPCR. R.M., K.S., R.D.T. and L.C.L. performed SNP, DNA methylation and RNA-seq studies and bioinformatic analysis of the data. R.C.O., Y.H., M.D.S., M.H., J.R.N., R.C. and J.R.E. conducted MethylC-seq studies. H.M., R.M., R.C.O., Y.H., J.R.E., L.C.L., D.P.W. and S.M. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Joseph R. Ecker or Louise C. Laurent or Shoukhrat Mitalipov.

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Supplementary information

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  1. 1.

    Supplementary Information

    This file contains Supplementary Tables 1-4.

Excel files

  1. 1.

    Supplementary Table 5

    List of CD DMRs

  2. 2.

    Supplementary Table 6

    List of non-CG mega-DMRs

  3. 3.

    Supplementary Table 7

    GO analysis results for genes within non-CG mega-DMRs

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