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Cell Rep. 2016 Jul 12;16(2):559-570. doi: 10.1016/j.celrep.2016.05.091. Epub 2016 Jun 23.

5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells.

Author information

1
Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden. Electronic address: colm.nestor@liu.se.
2
Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden.
3
Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden.
4
MD Anderson Cancer Center, Houston, TX 77030, USA.
5
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
6
Genomatix Software GmbH, 80335 Munich, Germany.
7
Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany.
8
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.
9
Centre for Personalized Medicine, Department of Pediatrics, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden. Electronic address: mikael.benson@liu.se.

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.

PMID:
27346350
PMCID:
PMC5868728
DOI:
10.1016/j.celrep.2016.05.091
[Indexed for MEDLINE]
Free PMC Article

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