Imprint Instability in Mammalian Reproduction

Timothy Bestor

Genomic imprints are established during gametogenesis (in growing dictyate oocytes in the female and in premeiotic prospermatogonia in the male) and are required for monoallelic expression of imprinted loci in somatic tissues of the next generation. A protein called DNMT3L, which is distantly related to DNMT3A and DNMT3B, is present only in preimplantation embryos and in germ cells at the stages where genomic imprints are established. Gene disruption experiments showed that DNMT3L is required for the establishment of maternal genomic imprints. An oocyte-specific form of DNMT1 (DNMT1o) is required for the maintenance of imprints at one cell cycle of preimplantation development but is otherwise dispensable. Mutations in DNMT3L and DNMT1o behave as maternal effect mutations. These findings are of significance to cloning by nuclear transfer because somatic nuclei contain a form of DNMT1 that is not present in preimplantation embryos and lack the DNMT3L that is normally present in early embryos. The instability of genomic imprints and the unpredictable phenotypic diversity in clonal offspring may arise from incompatibility of the DNA methylating systems of somatic cells and early embryos. Success in cloning by nuclear transfer will require attention to imprint maintenance during early development.