ADULT PHENOTYPE IN THE MOUSE CAN BE AFFECTED BY EPIGENETIC EVENTS IN THE EARLY EMBRYO

Major epigenetic modifications apparently occur during early developme nt in the mouse. The factors that induce such modifications are comple x and may involve the various components of a zygote. We have started to explore whether changes in the nucleocytoplasmic composition brough t about by micromanipulation can induce phenotypic effects through epi genetic modifications. Nucleocytoplasmic hybrids were therefore prepar ed by transplanting a female pronucleus into a recipient egg from a di fferent genotype. As a result, the maternal genome was of a different genetic background as compared with the egg cytoplasm. Specifically, e xperimental zygotes had cytoplasm from the inbred strain C57BL/6, a ma ternal genome from DBA/2, and a paternal genome from C57BL/6 (termed B DB hybrids). The mirror-image combination, termed DBD, was also made. The reconstituted zygotes were transferred to recipients and allowed t o develop to term. Mice born from manipulated zygotes showed transcrip tional repression and DNA methylation of major urinary protein genes i n their liver, as well as growth deficiency resulting in reduced adult body weight. No altered phenotype was observed in controls in which t he maternal pronucleus was simply transplanted back into another zygot e of the same genetic background. These results clearly demonstrate ph enotypic as well as molecular effects on DNA methylation and expressio n of at least one gene. Phenotype was therefore no longer predicted by genotype as a result of epigenetic modifications in experimental embr yos. What precisely triggers the phenotypic and epigenetic changes is unknown, but presumably, nucleocytoplasmic interactions in hybrid zygo tes may be partly responsible.