| First Author | Li Z | Year | 2020 |
| Journal | Nature | Volume | 583 |
| Issue | 7817 | Pages | 625-630 |
| PubMed ID | 32669713 | Mgi Jnum | J:292119 |
| Mgi Id | MGI:6446266 | Doi | 10.1038/s41586-020-2500-9 |
| Citation | Li Z, et al. (2020) N(6)-methyladenine in DNA antagonizes SATB1 in early development. Nature 583(7817):625-630 |
| abstractText | The recent discovery of N(6)-methyladenine (N(6)-mA) in mammalian genomes suggests that it may serve as an epigenetic regulatory mechanism(1). However, the biological role of N(6)-mA and the molecular pathways that exert its function remain unclear. Here we show that N(6)-mA has a key role in changing the epigenetic landscape during cell fate transitions in early development. We found that N(6)-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 N(6)-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 N(6)-mA also antagonizes SATB1 function in vivo by preventing its binding to chromatin. Concordantly, N(6)-mA functions at the boundaries between euchromatin and heterochromatin to restrict the spread of euchromatin. Repression of SIDD-SATB1 interactions mediated by N(6)-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 N(6)-mA function via SATB1, and reveal connections between DNA modification, DNA secondary structures and large chromatin domains in early embryonic development. |
