N-methyladenine in DNA antagonizes SATB1 in early development
Authors: Yinsheng Wang
Pengcheng Wang
Cheng Guo
Min Zhang
Tao P Wu
Zongliang Jiang
Myles H Alderman 3rd
Andrew Z Xiao
Shuai Zhao
Wang Min
Raman V Nelakanti
Zheng Li
Haitao Li
Kaixuan Lin
Journal: Nature (2020)
Discipline: Multidisciplinary
Keywords: N6-methyladenine; epigenetic regulation; cell fate transitions; trophoblast stem cells; stress-induced DNA double helix destabilization (SIDD)
Affiliations: Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA., MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China., Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Department of Chemistry, University of California, Riverside, CA, USA., Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT, USA., School of Animal Sciences, AgCenter, Louisiana State University, Baton Rouge, LA, USA., MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China. ., Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA. .

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. 

Retracted: No

PubPeer comments:
 The conclusions of this paper should be viewed with extreme skepticism! The authors failed to account for, or even cite recent work clearly showing that detection of 6mA in mammalian DNA is artifactual, and can be explained by methodological flaws and sources of contamination inherent to commonly used 6mA detection and mapping methods: https: www.ncbi.nlm.nih.gov pmc articles PMC7080441 https: www.ncbi.nlm.nih.gov pmc articles PMC6625966 https: pubmed.ncbi.nlm.nih.gov 31159718 ,