N6-methyladenine in DNA antagonizes SATB1 in early development

Zheng Li, Shuai Zhao, Raman V. Nelakanti, Kaixuan Lin, Tao P. Wu, Myles H. Alderman, Cheng Guo, Pengcheng Wang, Min Zhang, Wang Min, Zongliang Jiang, Yinsheng Wang, Haitao Li () and Andrew Z. Xiao ()
Additional contact information
Zheng Li: Yale School of Medicine
Shuai Zhao: Tsinghua University
Raman V. Nelakanti: Yale School of Medicine
Kaixuan Lin: Yale School of Medicine
Tao P. Wu: Yale School of Medicine
Myles H. Alderman: Yale School of Medicine
Cheng Guo: University of California
Pengcheng Wang: University of California
Min Zhang: Tsinghua University
Wang Min: Yale University School of Medicine
Zongliang Jiang: Louisiana State University
Yinsheng Wang: University of California
Haitao Li: Tsinghua University
Andrew Z. Xiao: Yale School of Medicine

Nature, 2020, vol. 583, issue 7817, 625-630

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2500-9

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