N(6)-methyladenine in DNA antagonizes SATB1 in early development

• Published in: Nature (London) Vol. 583; no. 7817; pp. 625 - 630
• Main Authors: Li, Zheng, Zhao, Shuai, Nelakanti, Raman V., Lin, Kaixuan, Wu, Tao P., Alderman, Myles H., Guo, Cheng, Wang, Pengcheng, Zhang, Min, Min, Wang, Jiang, Zongliang, Wang, Yinsheng, Li, Haitao, Xiao, Andrew Z.
• Format: Journal Article
• Language: English
• Published: 23.07.2020
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-2500-9

The recent discovery of 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 molecular pathways exerting its function remain elusive. Herein, we demonstrate that N 6 -mA plays a critical role in changing the epigenetic landscape during cell fate transitions in early development. We found that N 6 -mA is upregulated during trophoblast stem cell development, specifically at S tress I nduced D NA Double Helix D estabilization (SIDD) regions 2 - 4 . It is well-known that SIDD regions are conducive to topological stress-induced double helix unpairing and play critical roles in organizing large-scale chromatin structures 3 , 5 , 6 . We demonstrated that the presence of N 6 -mA abolishes (>500-fold) the in vitro interactions between SIDD and SATB1, a critical chromatin organizer interacting with SIDD regions; N 6 -mA deposition also effectively antagonizes SATB1 function in vivo by preventing its binding to chromatin. Concordantly, N 6 -mA functions at the boundaries between eu-/hetero- chromatin to restrict the spreading of euchromatin. N 6 -mA mediated repression is critical for gene regulation during trophoblast development in cell culture models and in vivo . Overall, our study discovers an unexpected molecular mechanism for N 6 -mA function via SATB1, and reveals surprising connections between DNA modification, DNA secondary structures and large chromatin domains in early embryonic development.