N6-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: London Nature Publishing Group UK 23.07.2020; Nature Publishing Group
• Subjects: 45/100; 45/15; 45/23; 45/91; 631/208/176/2016; 631/337/176/1988; 631/532/2442; Cell culture; Cell fate; Chromatin; Deoxyribonucleic acid; Destabilization; DNA; Embryogenesis; Embryonic growth stage; Epigenetics; Euchromatin; Gene expression; Gene regulation; Genomes; Heterochromatin; Humanities and Social Sciences; Mitochondrial DNA; Molecular modelling; multidisciplinary; N6-methyladenosine; Regulatory mechanisms (biology); Science; Science (multidisciplinary); Stem cell transplantation; Stem cells
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-2500-9

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. The DNA modification N 6 -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.