Chromatin and sequence features that define the fine and gross structure of genomic methylation patterns
- John R. Edwards1,8,
- Anne H. O'Donnell2,8,
- Robert A. Rollins3,
- Heather E. Peckham4,
- Clarence Lee4,
- Maria H. Milekic5,
- Benjamin Chanrion6,
- Yutao Fu4,
- Tao Su7,
- Hanina Hibshoosh7,
- Jay A. Gingrich5,
- Fatemeh Haghighi6,
- Robert Nutter4 and
- Timothy H. Bestor2,9
- 1 Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 2 Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA;
- 3 Center for Integrative Biology and BioTherapeutics, Pfizer BioTherapeutics Research and Development, Pearl River, New York 10965, USA;
- 4 Life Technologies, Beverly, Massachusetts, 01915 and Foster City, California 94404, USA;
- 5 Department of Psychology and the Sackler Institute of Developmental Neuroscience, Columbia University and the New York State Psychiatric Institute, New York, New York 10032, USA;
- 6 Division of Molecular Imaging and Neuropathology and the Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, New York, New York 10032, USA;
- 7 Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA
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↵8 These authors contributed equally to this work.
Abstract
Abnormalities of genomic methylation patterns are lethal or cause disease, but the cues that normally designate CpG dinucleotides for methylation are poorly understood. We have developed a new method of methylation profiling that has single-CpG resolution and can address the methylation status of repeated sequences. We have used this method to determine the methylation status of >275 million CpG sites in human and mouse DNA from breast and brain tissues. Methylation density at most sequences was found to increase linearly with CpG density and to fall sharply at very high CpG densities, but transposons remained densely methylated even at higher CpG densities. The presence of histone H2A.Z and histone H3 di- or trimethylated at lysine 4 correlated strongly with unmethylated DNA and occurred primarily at promoter regions. We conclude that methylation is the default state of most CpG dinucleotides in the mammalian genome and that a combination of local dinucleotide frequencies, the interaction of repeated sequences, and the presence or absence of histone variants or modifications shields a population of CpG sites (most of which are in and around promoters) from DNA methyltransferases that lack intrinsic sequence specificity.
Footnotes
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↵9 Corresponding author.
E-mail THB12{at}columbia.edu.
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[Supplemental material is available online at http://www.genome.org. The methylation data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE21242.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.101535.109.
- Received October 6, 2009.
- Accepted April 12, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press