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Whole-genome fingerprint of the DNA methylome during human B cell differentiation.

ABSTRACT: We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.

SUBMITTER: Kulis M

PROVIDER: S-EPMC5444519 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Whole-genome fingerprint of the DNA methylome during human B cell differentiation.

Kulis Marta M Merkel Angelika A Heath Simon S Queirós Ana C AC Schuyler Ronald P RP Castellano Giancarlo G Beekman Renée R Raineri Emanuele E Esteve Anna A Clot Guillem G Verdaguer-Dot Néria N Duran-Ferrer Martí M Russiñol Nuria N Vilarrasa-Blasi Roser R Ecker Simone S Pancaldi Vera V Rico Daniel D Agueda Lidia L Blanc Julie J Richardson David D Clarke Laura L Datta Avik A Pascual Marien M Agirre Xabier X Prosper Felipe F Alignani Diego D Paiva Bruno B Caron Gersende G Fest Thierry T Muench Marcus O MO Fomin Marina E ME Lee Seung-Tae ST Wiemels Joseph L JL Valencia Alfonso A Gut Marta M Flicek Paul P Stunnenberg Hendrik G HG Siebert Reiner R Küppers Ralf R Gut Ivo G IG Campo Elías E Martín-Subero José I JI

Nature genetics 20150608 7

We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregul ...[more]

PMID: 26053498

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Project description:BackgroundBreast intraductal papilloma (IP) is mainly caused by the abnormal proliferation of ductal epithelial cells. Tree shrews have potential as an animal model for the study of breast tumours; however, little is known regarding the transcriptome and DNA methylome landscapes of breast IP in tree shrews. In this research, we conducted whole-genome DNA methylation and transcriptome analyses of breast IP and normal mammary glands in tree shrews.MethodsDNA methylation profiles were generated from the whole-genome bisulfite sequencing and whole-transcriptome landscapes of IP and control groups of tree shrews through strand-specific library construction and RNA sequencing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses and gene set enrichment analysis were performed. Spearman's correlation analysis was used to identify statistical relationships between gene expression and DNA methylation.ResultsA genome-wide perspective of the epigenetic regulation of protein-coding genes in breast IP in tree shrews was obtained. The methylation levels at CG sites were considerably higher than those at CHG or CHH sites, and were highest in gene body regions. In total, 3,486, 82 and 361 differentially methylated regions (DMRs) were identified in the context of CG, CHG, and CHH, respectively, and 701 differentially methylated genes (DMGs) were found. Further, through transcriptomic analysis, 62 differentially expressed genes, 50 long noncoding RNAs, and 32 circular RNAs were identified in breast IP compared to normal mammary glands. Correlation analysis between the DNA methylation and transcriptome data revealed that 25 DMGs were also differentially expressed genes, among which the expression levels of 9 genes were negatively correlated with methylation levels in gene body regions. Importantly, integrated analysis identified 3 genes (PDZ domain-containing 1, ATPase plasma membrane Ca2+ transporting 4 and Lymphocyte cytosolic protein 1) that could serve as candidates for further study of breast IP in tree shrews.ConclusionsThis research has unearthed the comprehensive landscape of the transcriptome and DNA methylome of spontaneous IP in tree shrews, as well as candidate tumorigenesis related genes in IP. These results will contribute to the use of tree shrews in animal models of breast tumours.

Dataset Information

Whole-genome fingerprint of the DNA methylome during human B cell differentiation.

Publications

Whole-genome fingerprint of the DNA methylome during human B cell differentiation.

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