DNA sequence and methylation prescribe the inside-out conformational dynamics and bending energetics of DNA minicircles
Autor: | Jejoong Yoo, Sangwoo Park, Christopher Maffeo, Taekjip Ha, Aleksei Aksimentiev |
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Rok vydání: | 2021 |
Předmět: |
Quantitative Biology::Biomolecules
AcademicSubjects/SCI00010 Base pair Nucleic acid sequence Computational Biology DNA Methylation Molecular Dynamics Simulation Biology Minicircle Quantitative Biology::Genomics DNA sequencing Chromatin chemistry.chemical_compound chemistry Genetics Biophysics Nucleic Acid Conformation Nucleosome Human genome DNA Circular DNA |
Zdroj: | Nucleic Acids Research |
ISSN: | 1362-4962 0305-1048 |
Popis: | Eukaryotic genome and methylome encode DNA fragments’ propensity to form nucleosome particles. Although the mechanical properties of DNA possibly orchestrate such encoding, the definite link between ‘omics’ and DNA energetics has remained elusive. Here, we bridge the divide by examining the sequence-dependent energetics of highly bent DNA. Molecular dynamics simulations of 42 intact DNA minicircles reveal that each DNA minicircle undergoes inside-out conformational transitions with the most likely configuration uniquely prescribed by the nucleotide sequence and methylation of DNA. The minicircles’ local geometry consists of straight segments connected by sharp bends compressing the DNA’s inward-facing major groove. Such an uneven distribution of the bending stress favors minimum free energy configurations that avoid stiff base pair sequences at inward-facing major grooves. Analysis of the minicircles’ inside-out free energy landscapes yields a discrete worm-like chain model of bent DNA energetics that accurately account for its nucleotide sequence and methylation. Experimentally measuring the dependence of the DNA looping time on the DNA sequence validates the model. When applied to a nucleosome-like DNA configuration, the model quantitatively reproduces yeast and human genomes’ nucleosome occupancy. Further analyses of the genome-wide chromatin structure data suggest that DNA bending energetics is a fundamental determinant of genome architecture. |
Databáze: | OpenAIRE |
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