Figure 4.

Methyltransferases set m⁶A marks on mRNAs to balance the expression levels of pluripotency genes and lineage commitment genes in naïve and primed states of the ESCs. In the naïve state, the expression level of the pluripotency genes is dominant over that of lineage commitment genes, while in the primed state, the trend exhibits the opposite. The m⁶A methyltransferase depletion in naïve pluripotent cells further up-regulates already highly abundant naïve pluripotency genes, while the lineage commitment genes remain at very low residual levels. As a result, cells stay in a “hypernaïve” pluripotent state and fail to progress into the primed state. If the methyltransferase depletion occurs in the primed state, the expression level of the differentiation priming markers is further boosted, which pushes cells above the critical threshold toward differentiation, leading to fast differentiation and/or cell death.