5-Methylation of Cytosine in CG:CG Base-Pair Steps: A Physicochemical Mechanism for the Epigenetic Control of DNA Nanomechanics

Yusufaly, Tahir; Li, Yun; Olson, Wilma K.

doi:10.1021/jp409887t

Cited by 24 publications

(28 citation statements)

References 33 publications

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“…Other modifications induce different patterns of structural change: for the central base pair these changes are typically smaller than for methylation, but for base pair steps much larger changes are found in some parameters. Most notable of these are slide, which changes by over 3 Å and roll (up to 17°) in the 3´ direction, in a similar way to that reported previously for smaller systems 17, 18 . Other parameters such as the width of the DNA strand, measured as the distance between C1´ nuclei, and virtual angles λ Y and λ R , which describe the pivoting of complementary bases in the base-pair plane, vary only slightly from the idealised values for B-DNA.…”

Section: Resultssupporting

confidence: 86%

“…Regarding epigenetic modifications in particular, Acosta-Silva et al 17 showed in this manner that methylation enhances stacking interactions, and can produce local distortions in base-pair step parameters, most notably slide. Yusufaly et al used similar calculations to show that methylation can induce over-twisting as well as softer modes for distortion from the global energy minimum 18 . We recently employed classical mechanics to examine not only the structure but also the flexibility of different DNA sequences with methyl and hydroxymethyl substituents 19 .…”

Section: Introductionmentioning

confidence: 99%

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Theoretical modelling of epigenetically modified DNA sequences

et al. 2015

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We report herein a set of calculations designed to examine the effects of epigenetic modifications on the structure of DNA. The incorporation of methyl, hydroxymethyl, formyl and carboxy substituents at the 5-position of cytosine is shown to hardly affect the geometry of CG base pairs, but to result in rather larger changes to hydrogen-bond and stacking binding energies, as predicted by dispersion-corrected density functional theory (DFT) methods. The same modifications within double-stranded GCG and ACA trimers exhibit rather larger structural effects, when including the sugar-phosphate backbone as well as sodium counterions and implicit aqueous solvation. In particular, changes are observed in the buckle and propeller angles within base pairs and the slide and roll values of base pair steps, but these leave the overall helical shape of DNA essentially intact. The structures so obtained are useful as a benchmark of faster methods, including molecular mechanics (MM) and hybrid quantum mechanics/molecular mechanics (QM/MM) methods. We show that previously developed MM parameters satisfactorily reproduce the trimer structures, as do QM/MM calculations which treat bases with dispersion-corrected DFT and the sugar-phosphate backbone with AMBER. The latter are improved by inclusion of all six bases in the QM region, since a truncated model including only the central CG base pair in the QM region is considerably further from the DFT structure. This QM/MM method is then applied to a set of double-stranded DNA heptamers derived from a recent X-ray crystallographic study, whose size puts a DFT study beyond our current computational resources. These data show that still larger structural changes are observed than in base pairs or trimers, leading us to conclude that it is important to model epigenetic modifications within realistic molecular contexts.

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Section: Resultssupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Theoretical modelling of epigenetically modified DNA sequences

et al. 2015

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“…Statistical analysis is performed on a non-redundant dataset of protein-bound DNA obtained from the Nucleic Acid Database 31 and reported in a previous publication 11 . From this dataset, a fourteen-parameter data vector is generated that characterizes the atomic configuration of the model complex illustrated in Figure 3.…”

Section: Principal Component Analysis Of the Sugar-phosphate Backbonementioning

confidence: 99%

Arginine-phosphate salt bridges between histones and DNA: Intermolecular actuators that control nucleosome architecture

Yusufaly

Singh

et al. 2014

The Journal of Chemical Physics

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Structural bioinformatics and van der Waals density functional theory are combined to investigate the mechanochemical impact of a major class of histone-DNA interactions, namely the formation of salt bridges between arginine residues in histones and phosphate groups on the DNA backbone. Principal component analysis reveals that the configurational fluctuations of the sugarphosphate backbone display sequence-specific directionality and variability, and clustering of nucleosomal crystal structures identifies two major salt-bridge configurations: a monodentate form in which the arginine end-group guanidinium only forms one hydrogen bond with the phosphate, and a bidentate form in which it forms two. Density functional theory calculations highlight that the combination of sequence, denticity, and salt-bridge positioning enable the histones to apply a tunable mechanochemical stress to the DNA via precise and specific activation of backbone deformations. The results suggest that selection for specific placements of van der Waals contacts, with high-precision control of the spatial distribution of intermolecular forces, may serve as an underlying evolutionary design principle for the structure and function of nucleosomes, a conjecture that is corroborated by previous experimental studies.

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“…168 DNA methylation increases the rigidity of the chromatin structure and disfavours the positioning of nucleosomes on DNA. 169,170 Splicing entropy. RNA maturation process includes the assembly of gene products through splicing machinery.…”

Section: Intracellularmentioning

confidence: 99%

Cellular identity at the single-cell level

2016

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A single cell creates surprising heterogeneity in a multicellular organism. While every organismal cell shares almost an identical genome, molecular interactions in cells alter the use of DNA sequences to modulate the gene of interest for specialization of cellular functions. Each cell gains a unique identity through molecular coding across the DNA, RNA, and protein conversions. On the other hand, loss of cellular identity leads to critical diseases such as cancer. Most cell identity dissection studies are based on bulk molecular assays that mask differences in individual cells. To probe cell-to-cell variability in a population, we discuss single cell approaches to decode the genetic, epigenetic, transcriptional, and translational mechanisms for cell identity formation. In combination with molecular instructions, the physical principles behind cell identity determination are examined. Deciphering and reprogramming cellular types impact biology and medicine.

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5-Methylation of Cytosine in CG:CG Base-Pair Steps: A Physicochemical Mechanism for the Epigenetic Control of DNA Nanomechanics

Cited by 24 publications

References 33 publications

Theoretical modelling of epigenetically modified DNA sequences

Theoretical modelling of epigenetically modified DNA sequences

Arginine-phosphate salt bridges between histones and DNA: Intermolecular actuators that control nucleosome architecture

Cellular identity at the single-cell level

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