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Regulation of the transcriptional program by DNA methylation during human αβ T-cell development

AuthorsRodríguez, Ramón M; García-León, María J. ; Toribio, María Luisa ; López-Larrea, Carlos
Issue Date14-Dec-2014
PublisherOxford University Press
CitationNucleic Acids Research 43: 760- 774 (2014)
Abstract© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. Thymocyte differentiation is a complex process involving well-defined sequential developmental stages that ultimately result in the generation of mature T-cells. In this study, we analyzed DNA methylation and gene expression profiles at successive human thymus developmental stages. Gain and loss of methylation occurred during thymocyte differentiation, but DNA demethylation was much more frequent than de novo methylation and more strongly correlated with gene expression. These changes took place in CpG-poor regions and were closely associated with T-cell differentiation and TCR function. Up to 88 genes that encode transcriptional regulators, some of whose functions in T-cell development are as yet unknown, were differentially methylated during differentiation. Interestingly, no reversion of accumulated DNA methylation changes was observed as differentiation progressed, except in a very small subset of key genes (RAG1, RAG2, CD8A, PTCRA, etc.), indicating that methylation changes are mostly unique and irreversible events. Our study explores the contribution of DNA methylation to T-cell lymphopoiesis and provides a fine-scale map of differentially methylated regions associated with gene expression changes. These can lay the molecular foundations for a better interpretation of the regulatory networks driving human thymopoiesis.
Identifiersdoi: 10.1093/nar/gku1340
issn: 1362-4962
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