Modeling G4s in chromatin context confirms partial nucleosome exclusion and reveals nucleosome-disrupting effects of the least selective G4 ligands

G-quadruplexes (G4s) are gaining increasing attention as possible regulators of chromatin packaging, and robust approaches to their studies in pseudo-native context are much needed. Here, we designed a simple in vitro model of G4-prone genomic DNA and employed it to elucidate the impact of G4s and G4-stabilizing ligands on nucleosome occupancy. We obtained two 226-bp dsDNA constructs composed of the strong nucleosome positioning sequence and an internucleosomal DNA-imitating tail. The tail was G4-free in the control construct and harbored a “strong” (stable) G4 motif in the construct of interest. An additional “weak” (semi-stable) G4 motif was found within the canonical nucleosome positioning sequence. Both G4s were confirmed by optical methods and 1H NMR spectroscopy. Electrophoretic mobility assays showed that the weak G4 motif did not obstruct nucleosome assembly, while the strong G4 motif in the tail sequence diminished nucleosome yield. Atomic force microscopy data and molecular modeling confirmed that the strong G4 was maintained in the tail of the correctly assembled nucleosome structure. Using both in vitro and in silico models, we probed three known G4 ligands and detected nucleosome-disrupting effects of the least selective ligand. Our results are in line with the negative correlation between stable G4s and nucleosome density, support G4 tolerance between regularly positioned nucleosomes, and highlight the importance of considering chromatin context when targeting genomic G4s.

Authors
Pavlova Iuliia1, 2 , Barinov Nikolay1 , Novikov Roman3, 4 , Severov Vjacheslav1 , Iudin Mikhail1, 2 , Vedekhina Tatiana1 , Larin Andrey1, 11 , Babenko Vladislav1, 11 , Aralov Andrey5 , Gnuchikh Evgeny6 , Sardushkin Makar7 , Klinov Dmitry 1, 8 , Tsvetkov Vladimir 1, 9, 10 , Varizhuk Anna1, 2, 11
Journal
Biochimie
Publisher
Elsevier B.V.
Language
English
Pages
8-21
Status
Published
Volume
204
Year
2023
Organizations
  • 1 Federal Research and Clinical Center of Physical-Chemical Medicine, Moscow, 119435, Russia
  • 2 Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia
  • 3 Engelhardt Institute of Molecular Biology, Moscow, 119991, Russia
  • 4 N.D. Zelinsky Institute of Organic Chemistry, Moscow, 19991, Russia
  • 5 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, 119435, Russia
  • 6 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia
  • 7 National Research Center Kurchatov Institute, Kurchatov Genomic Center, Moscow, 123182, Russia
  • 8 Mendeleev University of Chemical Technology of Russia, 125047, Moscow, Russia
  • 9 Peoples' Friendship University of Russia (RUDN University), 117198, Moscow, Russia
  • 10 Institute of Biodesign and Complex System Modeling, I.M. Sechenov First Moscow State Medical University, Moscow, 119991, Russia
  • 11 A.V. Topchiev Institute of Petrochemical Synthesis, Leninsky Prospect Str. 29, Moscow, 119991, Russia
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