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Dnmt3a2 expression during embryonic development is required for phenotypic stability

ABSTRACT: Proper function and switching of regulatory elements is essential for the development of vertebrates and is known to be controlled by DNA cytosine methylation. We used isoform-specific knockouts of the two known DNA methyltransferase variants, Dnmt3a1 and Dnmt3a2 to probe their roles in regulatory element methylation in embryogenesis and in postnatal development. Mouse embryos lacking Dnmt3a1 showed minimal loss of genomic methylation confirming that this isoform may not be directly involved in embryonic development. However, they were smaller than their littermates and died about 4 weeks after birth with considerable postnatal demethylation as has been previously reported. On the other hand, embryos lacking Dnmt3a2 showed widespread genomic hypomethylation which was particularly prevalent at enhancers, CTCF sites and imprinted genes. Interestingly these methylation deficits were largely repaired after birth, presumably by the remaining Dnmt3a1 isoform. The mice lacking Dnmt3a2 were viable; however, they showed an increased prevalence of sporadic abnormalities as previously observed at a low frequency in laboratory mice, including anophthalmia, hydrocephalus, hydronephrosis and male infertility phenotypes. Interestingly, hypomethylation of several imprinted genes was also observed in sperm which might explain the infertility phenotype. Therefore, the interaction between the two isoforms is developmentally regulated, with Dnmt3a2 playing a key role in ensuring the methylation states of enhancers, CTCF sites and imprinted genes, thereby reducing the likelihood of stochastic phenotypes emerging after birth.

ORGANISM(S): Mus musculus

PROVIDER: GSE295720 | GEO | 2025/07/30

REPOSITORIES: GEO

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