N6-methyladenine in DNA antagonizes SATB1 in early development

Nature. 2020 Jul;583(7817):625-630. doi: 10.1038/s41586-020-2500-9. Epub 2020 Jul 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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


  • Euchromatin
  • Matrix Attachment Region Binding Proteins
  • SATB1 protein, human
  • DNA
  • Adenine
  • 6-methyladenine