title: Mapping of Variable DNA Methylation Across Multiple Cell Types Defines a Dynamic Regulatory Landscape of the Human Genome.
abstract: DNA methylation is an important epigenetic modification involved in many biological processes and diseases. Many studies have mapped DNA methylation changes associated with embryogenesis, cell differentiation, and cancer at a genome-wide scale. Our understanding of genome-wide DNA methylation changes in a developmental or disease-related context has been steadily growing. However, the investigation of which CpGs are variably methylated in different normal cell or tissue types is still limited. Here, we present an in-depth analysis of 54 single-CpG-resolution DNA methylomes of normal human cell types by integrating high-throughput sequencing-based methylation data. We found that the ratio of methylated to unmethylated CpGs is relatively constant regardless of cell type. However, which CpGs made up the unmethylated complement was cell-type specific. We categorized the 26,000,000 human autosomal CpGs based on their methylation levels across multiple cell types to identify variably methylated CpGs and found that 22.6% exhibited variable DNA methylation. These variably methylated CpGs formed 660,000 variably methylated regions (VMRs), encompassing 11% of the genome. By integrating a multitude of genomic data, we found that VMRs enrich for histone modifications indicative of enhancers, suggesting their role as regulatory elements marking cell type specificity. VMRs enriched for transcription factor binding sites in a tissue-dependent manner. Importantly, they enriched for GWAS variants, suggesting that VMRs could potentially be implicated in disease and complex traits. Taken together, our results highlight the link between CpG methylation variation, genetic variation, and disease risk for many human cell types.
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108.
authors.forename: Junchen
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108 Department of Computer Science and Engineering, Washington University in St. Louis, Missouri 63130.
authors.forename: Michael
authors.initials: M
authors.lastname: Stevens
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108.
authors.forename: Daofeng
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63108.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Oltz
authors.affiliation: Department of Pediatrics, University of Buffalo, New York 14203.
authors.forename: James N
authors.initials: JN
authors.lastname: Jarvis
authors.affiliation: Department of Pediatrics, University of Buffalo, New York 14203.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Theodore
authors.initials: T
authors.lastname: Cicero
authors.affiliation: Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108 Department of Computer Science and Engineering, Washington University in St. Louis, Missouri 63130 twang@genetics.wustl.edu.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
mesh_terms: D002874:Chromosome Mapping; D018899:CpG Islands; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D009928:Organ Specificity / Q000235:genetics
chemical_list: D006657:Histones
keywords: DNA methylomes; methylCRF; methylation dynamics; regulatory elements