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          Institute: MPI für molekulare Genetik     Collection: Sequencing Group     Display Documents

ID: 466132.0, MPI für molekulare Genetik / Sequencing Group
DNA methylation analysis of chromosome 21 gene promoters at single base pair and single allele resolution.
Authors:Zhang, Yingying; Rohde, Christian; Tierlin, Sascha; Jurkowski, Tomasz P.; Bock, Christoph; Santacruz, Diana; Ragozin, Sergey; Reinhardt, Richard; Groth, Marco; Walter, Jörn; Jeltsch, Albert
Research Context:This work had been supported by the NGF2 program of the German Federal Ministry of Research and Education (BMBF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Date of Publication (YYYY-MM-DD):2009-03-27
Title of Journal:PLoS Genetics
Journal Abbrev.:PLoS genet
Issue / Number:3
Start Page:e1000438
End Page:e1000438
Full name of Issue-Editor(s):Dirk Schübeler, Friedrich Miescher Institute for Biomedical Research, Switzerland
Copyright:2009 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Differential DNA methylation is an essential epigenetic signal for gene regulation, development, and disease processes. We mapped DNA methylation patterns of 190 gene promoter regions on chromosome 21 using bisulfite conversion and subclone sequencing in five human cell types. A total of 28,626 subclones were sequenced at high accuracy using (long-read) Sanger sequencing resulting in the measurement of the DNA methylation state of 580427 CpG sites. Our results show that average DNA methylation levels are distributed bimodally with enrichment of highly methylated and unmethylated sequences, both for amplicons and individual subclones, which represent single alleles from individual cells. Within CpG-rich sequences, DNA methylation was found to be anti-correlated with CpG dinucleotide density and GC content, and methylated CpGs are more likely to be flanked by AT-rich sequences. We observed over-representation of CpG sites in distances of 9, 18, and 27 bps in highly methylated amplicons. However, DNA sequence alone is not sufficient to predict an amplicon's DNA methylation status, since 43% of all amplicons are differentially methylated between the cell types studied here. DNA methylation in promoter regions is strongly correlated with the absence of gene expression and low levels of activating epigenetic marks like H3K4 methylation and H3K9 and K14 acetylation. Utilizing the single base pair and single allele resolution of our data, we found that i) amplicons from different parts of a CpG island frequently differ in their DNA methylation level, ii) methylation levels of individual cells in one tissue are very similar, and iii) methylation patterns follow a relaxed site-specific distribution. Furthermore, iv) we identified three cases of allele-specific DNA methylation on chromosome 21. Our data shed new light on the nature of methylation patterns in human cells, the sequence dependence of DNA methylation, and its function as epigenetic signal in gene regulation. Further, we illustrate genotype–epigenotype interactions by showing novel examples of allele-specific methylation.
Comment of the Author/Creator:E-mail: j.walter@mx.uni-saarland.de (JW); a.jeltsch@jacobs-university.de (AJ)
External Publication Status:published
Document Type:Article
Communicated by:Richard Reinhardt
Affiliations:MPI für Informatik/Computational Biology and Applied Algorithmics
External Affiliations:1.School of Engineering and Science, Jacobs University Bremen, Bremen, Germany;
2.Institut für Genetik, FB Biowissenschaften, Universität des Saarlandes, Saarbrücken, Germany;
3.Leibniz-Institute for Age Research—Fritz-Lipmann-Institute, Jena, Germany.
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