The RNA m⁶A reader YTHDC1 silences retrotransposons and guards ES cell identity

The RNA modification N⁶-methyladenosine (m⁶A) has critical roles in many biological processes^1,2. However, the function of m⁶A in the early phase of mammalian development remains poorly understood. Here we show that the m⁶A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m⁶A-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target m⁶A RNAs act upstream of SETDB1 to repress retrotransposons and Dux, the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for m⁶A RNA and YTHDC1 in chromatin modification and retrotransposon repression.