Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice

TLDR

Genomic imprinting is regulated by differential methylation of the paternal and maternal genome, yet the mechanisms establishing parental imprinting during gametogenesis remain unknown. The study demonstrates that Dnmt3L, a catalytically inactive homolog of Dnmt3a/b, is essential for establishing maternal methylation imprints and proper expression of maternally imprinted genes. Dnmt3L interacts with and co‑localizes to Dnmt3a/b in nuclei, indicating it regulates imprinting through these de novo methyltransferases. Dnmt3a‑deficient mice fail to establish maternal imprints, and both Dnmt3a and Dnmt3L are required for spermatogenesis, supporting that Dnmt3L cooperates with Dnmt3 family enzymes to mediate de novo methylation of maternal imprinted genes in oocytes.

Abstract

Genomic imprinting is regulated by differential methylation of the paternal and maternal genome. However, it remains unknown how parental imprinting is established during gametogenesis. In this study, we demonstrate that Dnmt3L, a protein sharing homology with DNA methyltransferases, Dnmt3a and Dnmt3b, but lacking enzymatic activity, is essential for the establishment of maternal methylation imprints and appropriate expression of maternally imprinted genes. We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells, suggesting that Dnmt3L may regulate genomic imprinting via the Dnmt3 family enzymes. Consistent with this model, we show that [Dnmt3a–/–, Dnmt3b+/–] mice also fail to establish maternal methylation imprints. In addition, both Dnmt3a and Dnmt3L are required for spermatogenesis. Together, our findings suggest that Dnmt3L may cooperate with Dnmt3 family methyltransferases to carry out de novo methylation of maternally imprinted genes in oocytes.