Specifically bound BZIP transcription factors modulate DNA supercoiling transitions

Abstract

Torsional stress on DNA, introduced by molecular motors, constitutes an important regulatory mechanism of transcriptional control. Torsional stress can modulate specific binding of transcription factors to DNA and introduce local conformational changes that facilitate the opening of promoters and nucleosome remodelling. Using all-atom microsecond scale molecular dynamics simulations together with a torsional restraint that controls the total twist of a DNA fragment, we address the impact of torsional stress on DNA complexation with a human BZIP transcription factor, MafB. We gradually over- and underwind DNA alone and in complex with MafB by 0.5° per dinucleotide step, starting from the relaxed state to a maximum of 5° per dinucleotide step, monitoring the evolution of the protein-DNA contacts at different degrees of torsional strain. Our computations show that MafB changes the DNA sequence-specific response to torsional stress. The dinucleotide steps that are susceptible to absorbing most of the torsional stress become more torsionally rigid, as they are involved in protein-DNA contacts. Also, the protein undergoes substantial conformational changes to follow the stress-induced DNA deformation, but mostly maintains the specific contacts with DNA. This results in a significant asymmetric increase of free energy of DNA twisting transitions, relative to free DNA, where overtwisting is more energetically unfavourable. Our data suggest that specifically bound BZIP factors could act as torsional stress insulators, modulating the propagation of torsional stress along the chromatin fibre, which might promote cooperative binding of collaborative DNA-binding factors.

Sequence-specific dynamics of DNA response elements and their flanking sites regulate the recognition by AP-1 transcription factors

“…Together with writhe, twist modulates DNA supercoiling transitions along the chromatin fibre. Recently, we have shown that MafB (a member of human BZIP family) ( 11 ), asymmetrically changes the sequence-specific response of DNA to torsional stress, making DNA effectively more rigid. The molecular mechanism of the observed phenomenon is based upon MafB forming a number of specific contacts with the torsionally flexible YR dinucleotide steps thus restraining their shift.…”

“…In addition, we know from the previous studies ( 14 , 52 , 53 ) that change in shift brings changes in twist, important for the regulation of DNA supercoiling transitions and, by extension, transcriptional control. Thus, the level of adjustment of bp shift when a transcription factor is bound to DNA directly translates into DNA local twist flexibility, and consequently the energetic cost of DNA supercoiling transitions ( 11 ). The described molecular mechanism, we hypothesise, allows the transcription factor to regulate the opening of gene promoters and subsequently their firing potentials, and by extension, the gene expression levels.…”

“…Subsequently, Curves+, Canal, and Canion programs ( 40 ) are used to derive the helical parameters, backbone torsional angles, groove geometry parameters, and ion distributions for each trajectory snapshot extracted every ps. CPPTRAJ is used to derive Yap1–DNA contacts as previously described ( 9 , 11 ). Free energy analysis for each system is performed using the MMPBSA/MMGBSA plugin in AMBERTOOLS 16.…”

“…The binding of AP-1 factors induce no major DNA deformation ( 3 , 10 ), as observed in experimentally solved structures of AP-1 protein–DNA complexes, however the proteins can potentially exploit local sequence-specific structural variations of DNA ( 11 ). The early analysis of crystallographic structures of protein–DNA complexes, by Olsson and colleagues ( 12 ), proposed that the most polymorphic pyrimidine(Y)-purine(R) dinucleotide steps could act as flexible ‘hinges’ facilitating the conformational adjustment of DNA to its protein-partner.…”

Homologous BHLH transcription factors induce distinct deformations of torsionally-stressed DNA: a potential transcription regulation mechanism

“…(Liebl and Zacharias 2020) To complete the picture of how torsional strain contributes to eukaryotic transcriptional control, we must also understand how torsional strain impacts DNA specific binding by transcription factor proteins. (Noy, Sutthibutpong, and A. Harris 2016;Pyne et al 2021;J. Hörberg and Reymer 2020) Locally DNA responds to torsional strain in a highly sequence-specific manner.…”