Adult phenotype in the mouse can be affected by epigenetic events in the early embryo

Abstract

Major epigenetic modifications apparently occur during early development in the mouse. The factors that induce such modifications are complex and may involve the various components of a zygote. We have started to explore whether changes in the nucleocytoplasmic composition brought about by micromanipulation can induce phenotypic effects through epigenetic modifications. Nucleocytoplasmic hybrids were therefore prepared by transplanting a female pronucleus into a recipient egg from a different genotype. As a result, the maternal genome was of a different genetic background as compared with the egg cytoplasm. Specifically, experimental zygotes had cytoplasm from the inbred strain C57BL/6, a maternal genome from DBA/2, and a paternal genome from C57BL/6 (termed BDB hybrids). The mirror-image combination, termed DBD, was also made. The reconstituted zygotes were transferred to recipients and allowed to develop to term. Mice born from manipulated zygotes showed transcriptional repression and DNA methylation of major urinary protein genes in their liver, as well as growth deficiency resulting in reduced adult body weight. No altered phenotype was observed in controls in which the maternal pronucleus was simply transplanted back into another zygote of the same genetic background. These results clearly demonstrate phenotypic as well as molecular effects on DNA methylation and expression of at least one gene. Phenotype was therefore no longer predicted by genotype as a result of epigenetic modifications in experimental embryos. What precisely triggers the phenotypic and epigenetic changes is unknown, but presumably, nucleocytoplasmic interactions in hybrid zygotes may be partly responsible.

Epigenetic Mechanisms Affecting Regulation of Energy Balance: Many Questions, Few Answers

“…Given the lack of coordination between the methylation and expression changes, and that methylation was not also assessed at weaning, these data do not provide strong evidence that hepatic DNA methylation changes act as a primary imprint to perpetuate persistent effects of exposure to maternal obesity. Interestingly, however, among the most strongly upregulated genes (51) were the major urinary proteins, in which, more than 20 years ago, long-term consequences of early environment on epigenetic regulation were demonstrated in liver of mice derived from nucleocytoplasmic hybrids (76). A related study in a sheep model employed embryo transfer at seven days of gestation (E7) to study the persistent effects of embryonic exposure to maternal obesity during the periconceptional period only (66).…”

Limited demethylation leaves mosaic-type methylation states in cloned bovine pre-implantation embryos

“…On the other hand, housekeeping genes remain unmethylated in all cells (Bird, 1986), except for X‐linked housekeeping genes, which are methylated on the inactive X chromosome in female cells and imprinted genes that show allele‐specific methylation patterns (Razin and Cedar, 1994). Another demethylation–remethylation cycle of epigenetic reprogramming takes place during gametogenesis and is necessary for resetting of imprints (Chaillet et al ., 1991; Stoger et al ., 1993; Ariel et al ., 1995; Tremblay et al ., 1995; Zuccotti and Monk, 1995) or, probably, for the removal of acquired epigenetic modifications, which can be influenced by individual genetic and environmental factors (Sapienza et al ., 1989; Allen et al ., 1990; Reik et al ., 1993).…”

IVM Advances for Early Antral Follicle-Enclosed Oocytes Coupling Reproductive Tissue Engineering to Inductive Influences of Human Chorionic Gonadotropin and Ovarian Surface Epithelium Coculture

“…However, techniques aimed at improving pronuclear manipulation and quality, as well as at optimizing the culture environment to help maintain embryo developmental potential, are still under investigation [ 122 ]. Some indications for the amelioration of embryo development might be obtained from oocyte pronuclear manipulation in mouse models where preliminary data postulate that abnormal pronuclear development could determine some detrimental epigenetic effects [ 123 , 124 ].…”