Journal Article Ppublish
PubMed: 40744496 DOI: 10.1093/nar/gkaf726
G-quadruplexes as potential traps for superenhancer marker BRD4: ligand-sensitive binding and co-separation in vitro.
Nucleic Acids Res 53(14)
Authors: Iuliia I Pavlova, Olga M Ivanova, Mikhail S Iudin, Anastasiya V Surdina, Nikolay A Barinov, Margarita E Bogomiakova, Sergey D Oreshkov, Zakhar O Shenkarev, Vjacheslav V Severov, Dmitriy V Klinov, Victoria O Shender, Alexandra N Bogomazova, Maria A Lagarkova, Anna M Varizhuk, Vladimir B Tsvetkov
Affiliations
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Malaya Pirogovskaya, 1a, 119435 Moscow, Russia.
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Malaya Pirogovskaya, 1a, 119435 Moscow, Russia.
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, 16/10 Miklukho-Maklaya St. 117997 Moscow, Russia.
- Center for Mathematical Modeling in Drug Development, Sechenov First Moscow State Medical University, 8-2 Trubetskaya, 119991 Moscow, Russia.
Abstract
G-quadruplexes (G4s) are prevalent at promoters and superenhancers (SEs), exclude nucleosomes, and recruit transcription factors. This study sought to determine whether the nucleosome exclusion affects the recruitment of the SE marker BRD4, which typically binds to acetylated histones and facilitates SE-promoter contacts via the phase separation-dependent mechanism. Analyses of the available whole-genome data revealed that SEs with the highest G4 density were depleted of nucleosomes but not of BRD4. This led us to test the possibility of histone-independent BRD4 maintenance at G4-rich SEs. A typical SE G4 destabilized a nearby nucleosome in vitro and, unlike B-DNA, bound weakly to BRD4 bromodomains. Similar to an acetylated nucleosome, the G4 promoted phase separation in BRD4 solutions. This effect was not altered by the histone competitor JQ1. However, it was attenuated by two known G4 ligands, suggesting that they could disrupt SE-promoter communication in cells. Consistently, these ligands downregulated several genes regulated by G4-rich SE-contacting promoters more efficiently than they did SE-independent genes. Our findings underscore the significance of G4-rich SEs as transcriptional regulators and provide new insights into their organization.
MeSH
Genes, Promoter Regions, Genetic, G-Quadruplexes, Nucleosomes, Histones, Nucleic Acids, Ligands