# The role of METTL3 in transposable elements regulation and 2C-like program induction in mouse embryonic stem cell

## TL;DR

This study shows that METTL3, an enzyme involved in RNA modification, regulates transposable elements and influences the developmental potential of mouse embryonic stem cells.

## Contribution

The study reveals METTL3's role in m6A-dependent regulation of transposable elements and 2C-like gene activation in mESCs.

## Key findings

- Mettl3 knockout in mESCs leads to upregulation of transposable elements and 2C-like genes.
- METTL3-deficient mESCs can contribute to trophectoderm lineages in blastocysts.
- m6A loss is linked to the acquisition of a 2C-like state with extended developmental potential.

## Abstract

METTL3 is a crucial mRNA methyltransferase in mammals, essential for the regulation of gene expression and various biological processes. Here, we demonstrate that Mettl3 knockout (KO) in mouse embryonic stem cells (mESCs) leads to widespread upregulation of transposable elements (TEs) and 2-cell (2C)-like genes in a m6A enzyme activity-dependent manner, independent of culture conditions. Furthermore, embryo chimera experiments using a transient METTL3 degradation system (dTAG) revealed that METTL3-deficient mESCs can contribute to trophectoderm lineages at the blastocyst stage, indicative of expanded developmental potential. These findings highlight the role of METTL3-mediated m6A modifications in regulating the transcriptional and developmental plasticity of mESCs and suggest a link between m6A loss and the acquisition of a 2C-like state with features of extended potency.

The online version contains supplementary material available at 10.1186/s13619-025-00262-w.