A sequence environment modulates the impact of methylation on the torsional rigidity of DNA

Hörberg, Johanna; Reymer, Anna

doi:10.1039/c8cc06550k

Cited by 16 publications

(23 citation statements)

References 19 publications

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“…steps to torsional stress ( Figure 2). In accordance with our previous studies 8,9 , the TpG and CpA steps of C-TpG-A and T-CpA-G motifs exhibit major torsional flexibility in free DNA, effectively absorbing both negative and positive torsional stress. The two tetranucleotide motifs are symmetrical, each belonging to the MARE-half site.…”

supporting

confidence: 91%

“…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 relaxed B-like conformation. The torsional plasticity of these dinucleotides is founded in the polymorphic nature of the DNA backbone.…”

mentioning

confidence: 99%

“…of the MARE-half sites. Since the helical parameters shift and twist are structurally coupled via the BI/BII backbone conformational transitions, 12,8,9 the protein-induced negative shift locks the TpG and CpA dinucleotides in a high twist substate. We monitor the evolution of the MafB-DNA contacts network to estimate the structural impact of changing torsional stress on the protein-DNA complex.…”

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confidence: 99%

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BZIP Transcription Factors Modulate DNA Supercoiling Transitions

Hörberg

Reymer

2019

Preprint

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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 ...

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confidence: 99%

mentioning

confidence: 99%

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BZIP Transcription Factors Modulate DNA Supercoiling Transitions

Hörberg

Reymer

2019

Preprint

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“…Moreover, changes in shift are coupled to changes in twist through DNA backbone BI → BII transitions; 14,48,49 therefore, we also observe an alteration of twist for Yap1-bound DNA. This observation is interesting in the context of DNA supercoiling and its role in eukaryotic transcriptional control.…”

Section: Helical Parametersmentioning

confidence: 58%

“…This, we suggest, will influence the binding affinity and allow the transcription factor to discriminate between different genomic locations containing the same response element. In addition, we know from the previous studies 14,48,49 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 b.p.…”

Section: Resultsmentioning

confidence: 99%

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

Hörberg

Moreau

Reymer

2020

Preprint

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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 dynamics for stability and specific binding of AP-1 factors, using microseconds 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 plasticity 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.

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Biophysics is reshaping our perception of the epigenome: from DNA-level to high-throughput studies

Kanapeckaitė¹,

Burokienė

Mažeikienė

et al. 2021

Biophysical Reports

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A sequence environment modulates the impact of methylation on the torsional rigidity of DNA

Abstract: We explain, with atomic-level detail, how DNA methylation may contribute to the regulation of biological processes. We show that DNA sequence environment modulates the impact of methylation on the physical properties of the double helix.

Cited by 16 publications

References 19 publications

BZIP Transcription Factors Modulate DNA Supercoiling Transitions

BZIP Transcription Factors Modulate DNA Supercoiling Transitions

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

Biophysics is reshaping our perception of the epigenome: from DNA-level to high-throughput studies

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