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 remodeling. Using all-atom microsecond scale molecular dynamics simulations together with a torsional restraint that controls the total helical twist of a DNA fragment, we addressed 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 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 absorb most of the torsional stress become more torsionally rigid, as they are involved in the protein-DNA contacts. Also, the protein undergoes substantial conformational changes to follow the stressinduced 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 unfavorable. Our data suggest that MafB could act as a torsional stress insulator, modulating the propagation of torsional stress along the chromatin fiber, which might promote cooperative binding of other transcription factors.Torsional restraints on DNA, referred to as DNA supercoiling, constantly change during the life of the cell, and regulate transcriptional control on many levels. 1-5 DNA supercoiling represents a sum of writhe and twist -the two interchangeable variables. DNA writhing generally dominates supercoiling changes on a larger scale through the formation of loops and knots, while DNA twisting occurs when shorter DNA fragments, up to ~100 base pairs (b.p.), experience changes in torsional restraints. The net state of genomic DNA is neutral, but regions of positive and negative supercoiling can exist locally, created by RNA polymerases that expose DNA to torsional stress. 3,5 This introduces DNA undertwisting (negative supercoiling) upstream and overtwisting (positive supercoiling) downstream of a transcribed gene.Torsional stress can propagate along DNA, modulating transcription of near-located genes 1,5 by altering the stability of nucleosomes and other protein-DNA complexes, 3,4,6,7 changing the accessibility of the genetic code. The ranges and speeds of torsional stress propagation depend on the underlying nucleotide sequence. 1 Computational experiments confirm: DNA responds to torsional stress in a heterogeneous and sequencedependent manner. 8,9 Certain dinucleotide steps, mainly pyrimidine-purine (YpR) but also purine-purine (RpR), in specific sequence environments, absorb a large part of DNA over-and undertwisting, while the rest of the molecule preserves its ...

Rational design of minimal synthetic promoters for plants

“…Several bZIP TFs have been shown to function as pioneer TFs, able to displace nucleosomes in chromatin inaccessible to other TFs, thus enabling the assembly of other TFs ( 62 , 63 ). It has recently been hypothesized that some bZIP proteins inhibit chromatin compaction, initiating the formation of enhanceosomes (higher-order multicomponent TF–enhancer complexes) ( 64 ). Optimal positioning of pioneer TFs, in particular, has been suggested to be necessary for gene expression ( 65 ), which could explain the significant impact of relocation (Figure 1C ).…”

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

“…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 believe, allows the transcription factor to regulate the opening of gene promoters and subsequently their firing potentials, and by extension, the gene expression levels.…”

“…50 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.…”

“…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. However, due to the limited number of protein-DNA structures, the study focused on the nearest-neighbour effects.…”

Rational Design of Minimal Synthetic Promoters for Plants

“…Several bZIP TFs have been shown to function as pioneer TFs, able to displace nucleosomes in chromatin inaccessible to other TFs, thus enabling the assembly of other TFs (59,60). It has recently been hypothesised that some bZIP proteins inhibit chromatin compaction, initiating the formation of enhanceosomes (higher-order multicomponent transcription factorenhancer complexes) (61). Optimal positioning of pioneer TFs, in particular, has been suggested to be necessary for gene expression (62), which could explain the significant impact of relocation ( Figure 1C).…”