The elusive Dnmt1 and its role during early development

Abstract

In mammals, DNA methylation serves a number of essential roles primarily in regulation of transcriptional silencing establishing a heritable and stable mark in each replication cycle. In the preimplantation mouse embryo, DNA methylation is modulated extensively resulting in an overall loss of methylation progressively up to the morula stage. Curiously some imprinted loci and their controlling regions, as well as specific repetitive sequences, are excluded from this genome-wide loss of DNA methylation suggesting that mechanisms to distinguish between CpG motifs must exist from the earliest stage of development. Mechanistically an oocyte-specific form of Dnmt1, Dnmt1o, is known to enter the nucleus at the 8-cell stage to maintain imprinted methylation marks although the identification of activities responsible both before and immediately after the 8-cell stage has remained elusive. The aim of this commentary is to highlight the major findings of two recent papers that address some of these present issues, and consequently move us towards a more comprehensive understanding of the mechanistic intricacies necessary to negotiate early development while maintaining imprinted methylation marks. Collectively the responsibility for maintenance of imprinted DNA methylation during early development is a shared partnership between Dnmt1 of maternal origin together with newly transcribed Dnmt1 of zygotic origin. Embryos null for Dnmt1 fail to survive beyond mid-gestation, highlighting the importantance of DNA methylation for normal growth and development to term. © 2008 Landes Bioscience.