Regulation of de novo and maintenance DNA methylation by DNA methyltransferases in post-implantation embryos.

Abstract

DNA methylation is mainly catalyzed by three DNA methyltransferase (DNMT) proteins in mammals. Usually DNMT1 is considered the primary DNMT for maintenance DNA methylation, whereas DNMT3A and DNMT3B function in de novo DNA methylation. Interestingly, we found DNMT3A and DNMT3B exerted maintenance and de novo DNA methylation in post-implantation mouse embryos. Together with DNMT1, they maintained DNA methylation at some pluripotent genes and lineage marker genes. Germline-derived DNA methylation at the imprinting control regions (ICRs) is stably maintained in embryos. DNMT1 maintained DNA methylation at most ICRs in post-implantation embryos. Surprisingly, DNA methylation was increased at five ICRs after implantation, and two DNMT3 proteins maintained the newly acquired DNA methylation at two of these five ICRs. Intriguingly, DNMT3A and DNMT3B maintained pre-existing DNA methylation at four other ICRs, similar to what we found in embryonic stem (ES) cells before. These results suggest that DNA methylation is more dynamic than originally thought during embryogenesis including the ICRs of the imprinted regions. DNMT3A and DNMT3B exert both de novo and maintenance DNA methylation functions after implantation. They maintain large portions of newly acquired DNA methylation at variable degrees across the genome in mouse embryos, together with DNMT1. Furthermore, they contribute to maintenance of pre-existing DNA methylation at a subset of ICRs as well as in the CpG islands (CGIs) and certain lineage marker gene. These findings may have some implications for the important roles of DNMT proteins in development and human diseases.