title: Regulation of the transcriptional program by DNA methylation during human αβ T-cell development.
abstract: 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.
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain.
authors.forename: Ramon M
authors.initials: RM
authors.lastname: Rodriguez
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Suarez-Alvarez
authors.affiliation: Genome Analysis Platform, CIC bioGUNE & CIBERehd, Technological Park of Bizkaia - Building 801A, 48160 Derio, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Mosén-Ansorena
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: García-Peydró
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fuentes
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: García-León
authors.affiliation: Genome Analysis Platform, CIC bioGUNE & CIBERehd, Technological Park of Bizkaia - Building 801A, 48160 Derio, Spain.
authors.forename: Aintzane
authors.initials: A
authors.lastname: Gonzalez-Lahera
authors.affiliation: Genome Analysis Platform, CIC bioGUNE & CIBERehd, Technological Park of Bizkaia - Building 801A, 48160 Derio, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Macias-Camara
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Toribio
authors.affiliation: Genome Analysis Platform, CIC bioGUNE & CIBERehd, Technological Park of Bizkaia - Building 801A, 48160 Derio, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aransay
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain Fundación Renal 'Íñigo Álvarez de Toledo', 28003 Madrid, Spain inmuno@hca.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Larrea
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D014157:Transcription Factors