Nature 583, 625–630 (2020)

N6-Methyladenine (N6-mA) is a DNA epigenetic mark present during early embryogenesis that can be removed by ALKBH1, a demethylase that prefers unpairing DNA substrates (SIDD). Given that Alkbh1-deficient mice exhibit extraembryonic defects particularly in the trophoblast, Li et al. examined the role of N6-mA during trophoblast development using an inducible embryonic stem cell system that transitions to trophoblast stem cell-like cells (TSC-LCs) and then differentiates into mature trophoblasts. N6-mA levels were elevated in TSC-LCs in which DNA exhibited unpairing (SIDD regions) and then declined in mature trophoblasts. The authors focused on the SIDD-binding protein SATB1 as a potential regulator of N6-mA, as SATB1 is highly upregulated during trophoblast stem cell development. Biochemical experiments demonstrated that SATB1 binding to DNA was blocked in the presence of N6-mA-modified DNA. ChIP-seq analysis showed that SATB1 DNA binding was reduced in regions in which N6-mA levels were enriched, while overexpression of ALKBH1 increased SATB1 binding. The competition between SATB1 and N6-mA regulates trophoblast cell fate, as overexpression of Alkbh1 increases TSC-LC differentiation whereas Satb1 deficiency blocks differentiation. Further work is needed to explore the function of this antagonistic relationship in other developmental and adult tissues.