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Mol. Hum. Reprod. Advance Access published online on October 11, 2005
Molecular Human Reproduction, doi:10.1093/molehr/gah230
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© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received April 18, 2005
Revised May 25, 2005
Accepted May 30, 2005

Article

IVF results in de novo DNA methylation and histone methylation at an Igf2-H19 imprinting epigenetic switch

Tao Li 1, Thanh H. Vu 1, Gary A. Ulaner 1, Eva Littman 2, Jian-Qun Ling 3, Hui-Ling Chen 3, Ji-Fan Hu 3, Barry Behr 4, Linda Giudice 4, and Andrew R. Hoffman 3*

1 Medical Service, VA Palo Alto Health Care System, Department of Medicine, Stanford University, Palo Alto, CA, USA; The authors equally contributed to this work
2 Department of Gynecology {wedge} Obstetrics, Stanford University, Palo Alto, CA, USA; The authors equally contributed to this work
3 Medical Service, VA Palo Alto Health Care System, Department of Medicine, Stanford University, Palo Alto, CA, USA
4 Department of Gynecology {wedge} Obstetrics, Stanford University, Palo Alto, CA, USA

* To whom correspondence should be addressed.
Andrew R. Hoffman, E-mail: arhoffman{at}stanford.edu


  Abstract

Recent studies suggest that IVF and assisted reproduction technologies (ART) may result in abnormal genomic imprinting, leading to an increased frequency of Angelman syndrome (AS) and Beckwith-Weidemann syndrome (BWS) in IVF children. To learn how ART might alter the epigenome, we examined morulas and blastocysts derived from C57BL/6J X M. spretus F1 mice conceived in vivo and in vitro and determined the allelic expression of four imprinted genes: Igf2, H19, Cdkn1c and Slc221L. IVFderived mouse embryos that were cultured in human tubal fluid (HTF) (Quinn’s advantage) media displayed a high frequency of aberrant H19 imprinting, whereas in vivo and IVF embryos showed normal maternal expression of Cdkn1c and normal biallelic expression of Igf2 and Slc221L. Embryonic stem (ES) cells derived from IVF blastocysts also showed abnormal Igf2/H19 imprinting. Allele-specific bisulphite PCR reveals abnormal DNA methylation at a CCCTC-binding factor (CTCF) site in the imprinting control region (ICR), as the normally unmethylated maternal allele acquired a paternal methylation pattern. Chromatin immunoprecipitation (ChIP) assays indicate an increase of lysine 4 methylation (dimethyl Lys4-H3) on the paternal chromatin and a gain in lysine 9 methylation (trimethyl Lys9-H3) on the maternal chromatin at the same CTCF-binding site. Our results indicate that de novo DNA methylation on the maternal allele and allele-specific acquisition of histone methylation lead to aberrant Igf2/H19 imprinting in IVF-derived ES cells. We suggest that ART, which includes IVF and various culture media, might cause imprinting errors that involve both aberrant DNA methylation and histone methylation at an epigenetic switch of the Igf2-H19 gene region.

Keywords: DNA methylation/embryonic stem cells/H19/Igf2/imprinting/IVF.
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