# Dnmt3a2 expression during embryonic development is required for phenotypic stability

## TL;DR

This study shows that Dnmt3a2 is essential for maintaining DNA methylation in regulatory elements during mouse embryonic development, preventing random birth defects.

## Contribution

The study reveals the distinct developmental roles of Dnmt3a isoforms, emphasizing Dnmt3a2's role in methylation and phenotypic stability.

## Key findings

- Dnmt3a2−/− mice show widespread hypomethylation at enhancers, CTCF sites, and imprinted genes during embryogenesis.
- Dnmt3a2−/− mice are viable but display sporadic abnormalities like anophthalmia and male infertility.
- Fertile Dnmt3a2−/− mice produce sperm with sporadic imprinting defects.

## Abstract

Proper function and switching of regulatory elements are essential for vertebrate development and are regulated by DNA methylation. We use isoform-specific knockouts of the de novo methyltransferase Dnmt3a1 and Dnmt3a2 to probe their roles during embryogenesis and postnatal development. Mice lacking Dnmt3a1 show minimal embryonic methylation loss but are smaller and die postnatally. In contrast, Dnmt3a2−/− mice exhibit widespread hypomethylation at enhancers, CTCF sites and imprinted genes, which are largely repaired postnatally. These mice are viable but display sporadic abnormalities including anophthalmia, hydrocephalus, hydronephrosis and male infertility due to absence of sperm. Interestingly, the fertile Dnmt3a2−/− mice produce sperm with sporadic imprinting defects. These findings suggest that the two isoform have distinct, developmentally regulated roles, with Dnmt3a2 being crucial for maintaining proper methylation of regulatory elements, especially for enhancers, CTCF sites and imprinted genes, and preventing stochastic phenotypic outcomes after birth.

Isoform-specific Dnmt3a knockouts reveal that Dnmt3a2 is required for proper methylation of enhancers, CTCF sites, and imprinted genes during early mouse embryonic development, thus decreasing stochastic developmental defects after birth.