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Epigenetics Chromatin. 2018 Feb 6;11(1):6. doi: 10.1186/s13072-018-0174-4.

Systematic prediction of DNA shape changes due to CpG methylation explains epigenetic effects on protein-DNA binding.

Rao S1, Chiu TP1, Kribelbauer JF2,3,4, Mann RS3,4,5,6, Bussemaker HJ7,8, Rohs R9,10,11,12.

Author information

1
Computational Biology and Bioinformatics Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
2
Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.
3
Department of Systems Biology, Columbia University, New York, NY, 10032, USA.
4
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, 10032, USA.
5
Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, 10027, USA.
6
Department of Neuroscience, Columbia University, New York, NY, 10027, USA.
7
Department of Biological Sciences, Columbia University, New York, NY, 10027, USA. hjb2004@columbia.edu.
8
Department of Systems Biology, Columbia University, New York, NY, 10032, USA. hjb2004@columbia.edu.
9
Computational Biology and Bioinformatics Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA, 90089, USA. rohs@usc.edu.
10
Department of Chemistry, University of Southern California, Los Angeles, CA, 90089, USA. rohs@usc.edu.
11
Department of Physics & Astronomy, University of Southern California, Los Angeles, CA, 90089, USA. rohs@usc.edu.
12
Department of Computer Science, University of Southern California, Los Angeles, CA, 90089, USA. rohs@usc.edu.

Abstract

BACKGROUND:

DNA shape analysis has demonstrated the potential to reveal structure-based mechanisms of protein-DNA binding. However, information about the influence of chemical modification of DNA is limited. Cytosine methylation, the most frequent modification, represents the addition of a methyl group at the major groove edge of the cytosine base. In mammalian genomes, cytosine methylation most frequently occurs at CpG dinucleotides. In addition to changing the chemical signature of C/G base pairs, cytosine methylation can affect DNA structure. Since the original discovery of DNA methylation, major efforts have been made to understand its effect from a sequence perspective. Compared to unmethylated DNA, however, little structural information is available for methylated DNA, due to the limited number of experimentally determined structures. To achieve a better mechanistic understanding of the effect of CpG methylation on local DNA structure, we developed a high-throughput method, methyl-DNAshape, for predicting the effect of cytosine methylation on DNA shape.

RESULTS:

Using our new method, we found that CpG methylation significantly altered local DNA shape. Four DNA shape features-helix twist, minor groove width, propeller twist, and roll-were considered in this analysis. Distinct distributions of effect size were observed for different features. Roll and propeller twist were the DNA shape features most strongly affected by CpG methylation with an effect size depending on the local sequence context. Methylation-induced changes in DNA shape were predictive of the measured rate of cleavage by DNase I and suggest a possible mechanism for some of the methylation sensitivities that were recently observed for human Pbx-Hox complexes.

CONCLUSIONS:

CpG methylation is an important epigenetic mark in the mammalian genome. Understanding its role in protein-DNA recognition can further our knowledge of gene regulation. Our high-throughput methyl-DNAshape method can be used to predict the effect of cytosine methylation on DNA shape and its subsequent influence on protein-DNA interactions. This approach overcomes the limited availability of experimental DNA structures that contain 5-methylcytosine.

KEYWORDS:

5-methylcytosine; DNA methylation; DNA structure; DNase I cleavage sensitivity; Epigenetics; Human Hox protein binding specificity; methyl-DNAshape

PMID:
29409522
PMCID:
PMC5800008
DOI:
10.1186/s13072-018-0174-4
[Indexed for MEDLINE]
Free PMC Article

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