Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology

Genomic imprinting in primate embryos and embryonic stem cells

Shoukhrat M. Mitalipov

Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA. Email:

Reproduction, Fertility and Development 18(8) 817-821
Submitted: 7 May 2006  Accepted: 4 September 2006   Published: 22 November 2006


Embryonic stem (ES) cells hold promise for cell and tissue replacement approaches to treating human diseases. However, long-term in vitro culture and manipulations of ES cells may adversely affect their epigenetic integrity including imprinting. Disruption or inappropriate expression of imprinted genes is associated with several clinically significant syndromes and tumorigenesis in humans. We demonstrated aberrant biallelic expression of IGF2 and H19 in several rhesus monkey ES cell lines while SNRPN and NDN were normally imprinted and expressed from the paternal allele. In contrast, expanded blastocyst-stage embryos, from which these ES cells were derived, exhibited normal paternal expression of IGF2 and maternal expression of H19. To test the possibility that aberrant methylation at an imprinting centre (IC) upstream of H19 accounts for the relaxed imprinting of IGF2 and H19, we performed comprehensive methylation analysis by investigating methylation profiles of CpG sites within the IGF2/H19 IC. Our results demonstrate abnormal hypermethylation within the IGF2/H19 IC in all analysed ES cell lines consistent with biallelic expression of these genes. Cellular overproliferation and tumour formation resulting from tissue or cell transplantation are potential problems that must be addressed before clinical trials of ES cell-based therapy are initiated.

Extra keywords: methylation, rhesus monkey.


Dean W.Bowden L.Aitchison A.Klose J.Moore T.Meneses J. J.Reik W.Feil R.1998Altered imprinted gene methylation and expression in completely ES cell-derived mouse fetuses: association with aberrant phenotypes.Development12522732282Pubmed Abstract

DeBaun M. R.Niemitz E. L.Feinberg A. P.2003Association of in vitro fertilization with Beckwith–Wiedemann syndrome and epigenetic alterations of LIT1 and H19.Am. J. Hum. Genet.72156160doi:10.1086/346031Pubmed Abstract

Doherty A. S.Mann M. R.Tremblay K. D.Bartolomei M. S.Schultz R. M.2000Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo.Biol. Reprod.6215261535doi:10.1095/BIOLREPROD62.6.1526Pubmed Abstract

El-Maarri O.Buiting K.Peery E. G.Kroisel P. M.Balaban al.2001Maternal methylation imprints on human chromosome 15 are established during or after fertilization.Nat. Genet.27341344doi:10.1038/85927Pubmed Abstract

Fujimoto A.Mitalipov S. M.Clepper L. L.Wolf D. P.2005Development of a monkey model for the study of primate genomic imprinting.Mol. Hum. Reprod.11413422doi:10.1093/MOLEHR/GAH180Pubmed Abstract

Fujimoto A.Mitalipov S. M.Kuo H. C.Wolf D. P.2006Aberrant genomic imprinting in rhesus monkey embryonic stem cells.Stem Cells24595603doi:10.1634/STEMCELLS.2005-0301Pubmed Abstract

Khosla S.Dean W.Brown D.Reik W.Feil R.2001Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes.Biol. Reprod.64918926doi:10.1095/BIOLREPROD64.3.918Pubmed Abstract

Maher E. R.Brueton L. A.Bowdin S. C.Luharia A.Cooper al.2003Beckwith–Wiedemann syndrome and assisted reproduction technology (ART).J. Med. Genet.406264doi:10.1136/JMG.40.1.62Pubmed Abstract

Mann M. R.Chung Y. G.Nolen L. D.Verona R. I.Latham K. E.Bartolomei M. S.2003Disruption of imprinted gene methylation and expression in cloned preimplantation stage mouse embryos.Biol. Reprod.69902914doi:10.1095/BIOLREPROD.103.017293Pubmed Abstract

Rugg-Gunn P. J.Ferguson-Smith A. C.Pedersen R. A.2005Epigenetic status of human embryonic stem cells.Nat. Genet.37585587doi:10.1038/NG1556Pubmed Abstract

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