title: 5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells.
abstract: 5-methylcytosine (5mC) is converted to 5-hydroxymethylcytosine (5hmC) by the TET family of enzymes as part of a recently discovered active DNA de-methylation pathway. 5hmC plays important roles in regulation of gene expression and differentiation and has been implicated in T cell malignancies and autoimmunity. Here, we report early and widespread 5mC/5hmC remodeling during human CD4(+) T cell differentiation ex vivo at genes and cell-specific enhancers with known T cell function. We observe similar DNA de-methylation in CD4(+) memory T cells in vivo, indicating that early remodeling events persist long term in differentiated cells. Underscoring their important function, 5hmC loci were highly enriched for genetic variants associated with T cell diseases and T-cell-specific chromosomal interactions. Extensive functional validation of 22 risk variants revealed potentially pathogenic mechanisms in diabetes and multiple sclerosis. Our results support 5hmC-mediated DNA de-methylation as a key component of CD4(+) T cell biology in humans, with important implications for gene regulation and lineage commitment.
authors.affiliation: Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden. Electronic address: colm.nestor@liu.se.
authors.forename: Colm E
authors.initials: CE
authors.lastname: Nestor
authors.affiliation: Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lentini
authors.affiliation: Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Hägg Nilsson
authors.affiliation: Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden.
authors.forename: Danuta R
authors.initials: DR
authors.lastname: Gawel
authors.affiliation: Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden.
authors.forename: Mika
authors.initials: M
authors.lastname: Gustafsson
authors.affiliation: Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Mattson
authors.affiliation: MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Rundquist
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
authors.affiliation: Genomatix Software GmbH, 80335 Munich, Germany.
authors.forename: Bernward
authors.initials: B
authors.lastname: Klocke
authors.affiliation: Genomatix Software GmbH, 80335 Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Seifert
authors.affiliation: Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.affiliation: Else Kröner-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, MRI and ZIEL, Technische Universität München, 85354 Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes at the Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, 85354 Freising-Weihenstephan, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Laumen
authors.affiliation: Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden. Electronic address: mikael.benson@liu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Benson
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D019175:DNA Methylation; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine