Aberrant DNA methylation of imprinted loci in superovulated oocytes

Sato, A.
Otsu, E.
Negishi, H.
Utsunomiya, T.
Arima, T.

¹St Luke Clinic, Tsumori, Oita, Japan
²Department of Molecular Genetics, Division of Molecular and Cell Therapeutics, Medical Institute of Bioregulation, Kyusyu University, Beppu, Oita, Japan

³To whom correspondence should be addressed at: Department of Molecular Genetics, Division of Molecular and Cell Therapeutics, Medical Institute of Bioregulation, Kyusyu University, 4546, Tsurumihara, Beppu, Oita 874-0838, Japan. E-mail: [email protected]

^*These authors contributed equally to this work.

Submitted on February 6, 2006; resubmitted on May 12, 2006, June 26, 2006; accepted on July 11, 2006

Human Reproduction 22(1):p 26-35, January 2007.

BACKGROUND

There is an increased incidence of rare imprinting disorders associated with assisted reproduction technologies (ARTs). The sex-specific epigenetic modifications that are imposed during gametogenesis act as a primary imprint to distinguish maternal and paternal alleles. The most likely candidate for the gametic mark is DNA methylation. However, the timing of DNA methylation acquisition in adult oocytogenesis and the effects of superovulation are unknown.

METHODS

We examined the maternal methylation of PEG1(MEST), LIT1(KCNQ1OT1) and ZAC(PLAGL1) and the paternal methylation of H19 in adult growing oocytes of humans and mice and compared them with the methylation status of mouse neonatal growing oocytes by using bisulphite sequencing. Furthermore, we examined the effects of superovulation in the human and mouse.

RESULTS

Maternal methylation of these genes has already been initiated to some extent in adult human and mouse non-growing oocytes but not in mouse neonates. In addition, the methylation dynamics during adult human and mouse oocyte development changed more gradually than those during neonatal oocyte development. Furthermore, we found the demethylation of PEG1 in growing oocytes from some ART-treated infertile women and a gain in the methylation of H19. We also detected methylation changes in superovulated mice.

CONCLUSION

Our studies in the human and mouse suggest that superovulation can lead to the production of oocytes without their correct primary imprint and highlight the need for more research into ARTs.