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

Abstract

Activator proteins 1 (AP-1) comprise one of the largest families of eukaryotic basic leucine zipper transcription factors. Despite advances in the characterization of AP-1 DNA-binding sites, our ability to predict new binding sites and explain how the proteins achieve different gene expression levels remains limited. Here we address the role of sequence-specific DNA flexibility for stability and specific binding of AP-1 factors, using microsecond-long molecular dynamics simulations. As a model system, we employ yeast AP-1 factor Yap1 binding to three different response elements from two genetic environments. Our data show that Yap1 actively exploits the sequence-specific flexibility of DNA within the response element to form stable protein–DNA complexes. The stability also depends on the four to six flanking nucleotides, adjacent to the response elements. The flanking sequences modulate the conformational adaptability of the response element, making it more shape-efficient to form specific contacts with the protein. Bioinformatics analysis of differential expression of the studied genes supports our conclusions: the stability of Yap1–DNA complexes, modulated by the flanking environment, influences the gene expression levels. Our results provide new insights into mechanisms of protein–DNA recognition and the biological regulation of gene expression levels in eukaryotes.

Methylation in NDUFA13 gene promoter disrupts communication between collaborative transcription factors – potential mechanism for onset of breast cancer

“…We continue with the analyses of protein-DNA contacts to further understand the mechanistic impact of CpG methylation on the E2F1-DP1-CEBPB-DNA enhanceosome formation. For the analyses we employ a dynamic contact map approach we derived earlier (41, 45), where for each MD frame we calculate a contact strength for every pair of protein-DNA residues that interact specifically and nonspecifically. We follow the time-evolution of the contacts strengths (Figures S5-S8) and calculate the average strength value for each protein-DNA contact (Figures 3, S9, S11, and S12).…”

“…Next, we analyze changes in DNA helical and groove parameters for the WT-vs ME-cases and solo-vs enhanceosome systems (Figures 5 and S19-S25). Previously, we reported that the binding of proteins to their response elements results in small conformational adjustments in DNA helical parameters, which facilitates formation of stable specific contacts (41). The changes are reflected in reducing the bimodality/multimodality and narrowing of the helical parameters’ distributions, indicating that proteins stabilize a particular DNA substate.…”

“…CPPTRAJ program from AMBERTOOLS 16 software package (40) is used for the analysis of protein-DNA contacts. We analyse both specific (hydrogen bonding and hydrophobic contacts) and nonspecific contacts (formed between either DNA or protein backbones) that are present for longer than 10% of the trajectory, see previous publication for details (41). Subsequently, Curves+, Canal, and Canion programs (42) are used to derive the helical parameters, backbone torsional angles, groove geometry parameters, and ion distributions for each trajectory snapshot extracted every ps.…”

Mechanical determinants of chromatin topology and gene expression

“…Evidently, DNA supercoiling changes the geometry of the double helix modulating the affinity of certain TFs to DNA. Conversely, TF binding by itself has the capacity to modify DNA response to supercoiling and modulate the affinity of other factors for their targets on the promoter [ 39 , 40 ]. Although it is well established that TF-DNA interactions is key to transcriptional control in eukaryotic cells, our understanding of the mechanistic and dynamic aspects of these interactions is still somewhat rudimentary.…”

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

“…The "twist-capacitors" dinucleotides, which include pyrimidine-purine (YpR) and purine-purine (RpR) steps, appear to regulate protein-DNA complexation, as twisting transitions are coupled to changes in shift and slide (Dans et al 2012;Pasi et al 2014;Dans et al 2019;Balaceanu et al 2019)-helical parameters important for the protein-DNA readout mechanism. (Johanna Hörberg et al 2021) Previously we addressed the impact of torsional strain on DNA complexation with a human basic-leucine-zipper (BZIP) transcription factor (TF) MafB.(J. Hörberg and Reymer 2020) When specifically bound to its DNA target, the protein locks the twist-capacitor dinucleotides in one conformational sub-state, favourable for the complexation.…”