N⁶-methyladenine in DNA antagonizes SATB1 in early development.

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 structures^3,5,6. 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.

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