The recent discovery of N6-methyladenine (N6-mA) in mammalian genomes suggests that it may serve as an epigenetic regulatory mechanism1. However, the biological role of N6-mA and the molecular pathways that exert its function remain unclear. Here we show that N6-mA has a key role in changing the epigenetic landscape during cell fate transitions in early development. We found that N6-mA is upregulated during the development of mouse trophoblast stem cells, specifically at regions of stress-induced DNA double helix destabilization (SIDD)2–4. Regions of SIDD are conducive to topological stress-induced unpairing of the double helix and have critical roles in organizing large-scale chromatin structures3,5,6. We show that the presence of N6-mA reduces the in vitro interactions by more than 500-fold between SIDD and SATB1, a crucial chromatin organizer that interacts with SIDD regions. Deposition of N6-mA also antagonizes SATB1 function in vivo by preventing its binding to chromatin. Concordantly, N6-mA functions at the boundaries between euchromatin and heterochromatin to restrict the spread of euchromatin. Repression of SIDD–SATB1 interactions mediated by N6-mA is essential for gene regulation during trophoblast development in cell culture models and in vivo. Overall, our findings demonstrate an unexpected molecular mechanism for N6-mA function via SATB1, and reveal connections between DNA modification, DNA secondary structures and large chromatin domains in early embryonic development. The DNA modification N6-methyladenine regulates gene expression during mouse trophoblast development by depositing at the boundaries of active chromatin and preventing its spread by antagonizing the chromatin organizer SATB1.

中文翻译：

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DNA中的N6-甲基腺嘌呤在早期发育中拮抗SATB1

最近在哺乳动物基因组中发现 N6-甲基腺嘌呤 (N6-mA) 表明它可能是一种表观遗传调控机制。然而，N6-mA 的生物学作用和发挥其功能的分子途径仍不清楚。在这里，我们展示了 N6-mA 在早期发育的细胞命运转变期间改变表观遗传景观方面具有关键作用。我们发现 N6-mA 在小鼠滋养层干细胞发育过程中上调，特别是在应激诱导的 DNA 双螺旋不稳定 (SIDD)2-4 区域。SIDD 区域有利于拓扑应力诱导的双螺旋不配对，并在组织大规模染色质结构中起关键作用 3,5,6。我们表明，N6-mA 的存在将 SIDD 和 SATB1 之间的体外相互作用降低了 500 倍以上，与 SIDD 区域相互作用的重要染色质组织者。N6-mA 的沉积还通过阻止 SATB1 与染色质的结合来拮抗体内的 SATB1 功能。一致地，N6-mA 在常染色质和异染色质之间的边界处起作用，以限制常染色质的传播。抑制由 N6-mA 介导的 SIDD-SATB1 相互作用对于细胞培养模型和体内滋养层发育过程中的基因调控至关重要。总体而言，我们的研究结果通过 SATB1 证明了 N6-mA 功能的一种意想不到的分子机制，并揭示了早期胚胎发育中 DNA 修饰、DNA 二级结构和大染色质结构域之间的联系。