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

In order to obtain genome-wide profiles, base-resolution methylomes of oocytes, 4-cells and blastocysts were generated using the bisulfite sequencing (BS-seq) method for few samples. We find that global loss of DNA methylation during preimplantation development in Ftdc1-/-and Ftdc2-/- mice. Such a loss of methylation upon Ftdc1 or Ftdc2 inactivation is truly global and occurs across all chromosomes and genomic features examined, such as exon, intron, transposon and etc. To refine the analysis, we identified 7,311 and 6,208 hypomethylated differentially methylated regions (hypo-DMRs) and no hypermethylated DMRs (hyper-DMRs) in Ftdc1- and Ftdc2-null blastocyst compared to WT, respectively. To test whether FTDC1/2 deficiency and the observed global hypomethylation have an impact on transcriptional activity, we conducted RNA-sequencing in WT and Ftdc1- or Ftdc2-null blastocysts. 1,886 and 1,073 differentially expressed genes were identified in Ftdc1-/-(up 945, down 941) and Ftdc2-/- embryos (up 945, down 941). Gene ontology (GO) analysis showed that these DEGs are primarily enriched in gastrulation, autophagy, adhesion, and immune system-related pathways. To assess the potential effects of FTDC1/2 deficiency on histone modifications, our genome-wide profiles of H3K9me3 in blastocysts revealed that FTDC1/2 depletion results in the massive loss of H3K9me3. In contrast, H3K9me3 was correspondingly reduced in those hypo-DMRs in Ftdc1-/- and Ftdc2-/- embryos.