FTDC1/2, oocyte-specific cofactors of DNMT1 required for epigenetic regulation and embryonic development

The unique epigenetic patterns during gametogenesis and embryonic development indicate the existence of specialized methylation machinery. In the present study, we describe the discovery of two oocyte-specific cofactors of DNA methyltransferase 1 (DNMT1), encoded by uncharacterized genes, ferritin domain containing 1 and 2 (Ftdc1 and Ftdc2). Genetic ablation of Ftdc1 or Ftdc2 causes midgestation defects and female infertility. FTDC1 or FTDC2 depletion induces the progressive loss of DNA methylation including imprinted regions in early embryos. This loss correlates with a marked reduction in DNMT1 protein due to increased degradation, likely via the ubiquitin-proteasome pathway. Mechanistically, we find that FTDC1, FTDC2 and DNMT1 form a complex by direct interactions, thereby stabilizing each other. Surprisingly, knockout of Ftdc1 or Ftdc2 displayed stronger DNA demethylation phenotypes and earlier embryonic lethality than the Dnmt1-null mutant, implying their unique functions. These data suggest that FTDC1/2 are crucial players specifically involved in maintaining genomic methylation during embryogenesis, offering new insights into the epigenetic control of mammalian development.