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Structural dynamics of double-stranded DNA with epigenome modification.

Ayako Furukawa1,2, Erik Walinda3, Kyohei Arita1

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Area of Science:

  • Biochemistry
  • Epigenetics
  • Molecular Biology

Background:

  • Cytosine modification is crucial for epigenetic regulation, influencing gene expression and genome stability.
  • DNA methyltransferases convert cytosine to 5-methylcytosine (5mC), which can be further oxidized to 5-hydroxymethylcytosine (5hmC).
  • DNA structural flexibility impacts protein binding to methylated DNA.

Purpose of the Study:

  • To analyze the dynamics of double-stranded DNA (dsDNA) with epigenetic modifications.
  • To compare base-opening and -closing rates in dsDNA with varying cytosine epigenetic states.
  • To understand how cytosine modifications affect DNA structural dynamics and base-pair stability.

Main Methods:

  • Utilized a semi-quantitative analysis combining imino 1H exchange and imino 1H R1ρ relaxation dispersion NMR experiments.
  • Characterized base-opening (kopen) and base-closing (kclose) rates for dsDNA.
  • Investigated dsDNA dynamics across different cytosine epigenetic modifications.

Main Results:

  • Identified distinct base-opening and -closing rates for dsDNA with various cytosine modifications.
  • Observed a significant increase in the base-opening rate (kopen) for hemi-methylated dsDNA (5mC/C) compared to unmodified or fully methylated dsDNA.
  • Demonstrated selective destabilization of GC Watson-Crick base pairs in hemi-methylated dsDNA.

Conclusions:

  • Epigenetic modulation of cytosine dynamics in dsDNA influences base-pair stability.
  • The increased base-opening rate in 5mC/C facilitates GC base-pair destabilization.
  • These findings suggest that epigenetic modifications mediate DNA structural changes, enabling base-flipping in cellular contexts.