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Title: N6-methyladenine in DNA antagonizes SATB1 in early development.

Authors: Li, Zheng; Zhao, Shuai; Nelakanti, Raman V; Lin, Kaixuan; Wu, Tao P; Alderman 3rd, Myles H; Guo, Cheng; Wang, Pengcheng; Zhang, Min; Min, Wang; Jiang, Zongliang; Wang, Yinsheng; Li, Haitao; Xiao, Andrew Z

Published In Nature, (2020 07)

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.

PubMed ID: 32669713 Exiting the NIEHS site

MeSH Terms: Adenine/analogs & derivatives*; Adenine/metabolism; Animals; Base Pairing; DNA/chemistry*; DNA/metabolism*; Embryonic Development*/genetics; Euchromatin/genetics; Euchromatin/metabolism; Female; Humans; Male; Matrix Attachment Region Binding Proteins/antagonists & inhibitors*; Matrix Attachment Region Binding Proteins/genetics; Matrix Attachment Region Binding Proteins/metabolism; Mice; Stem Cells/cytology; Stem Cells/metabolism; Thermodynamics; Trophoblasts/cytology

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