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5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0003-1239-5495
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 2, 559-570 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
CELL PRESS , 2016. Vol. 16, no 2, 559-570 p.
National Category
Cell and Molecular Biology
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URN: urn:nbn:se:liu:diva-131186DOI: 10.1016/j.celrep.2016.05.091ISI: 000380262300025PubMedID: 27346350OAI: oai:DiVA.org:liu-131186DiVA: diva2:971946
Note

Funding Agencies|Swedish Research Council; Ake Wibergs Foundation; Cancerfonden; Helmholtz Zentrum Munchen; Technische Universitat Munchen; Biotechnology and Biological Sciences Research Council (BBSRC); CEFIC; Medical Research Council (MRC)

Available from: 2016-09-19 Created: 2016-09-12 Last updated: 2016-09-19

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Nestor, ColmLentini, AntonioHägg Nilsson, CathrineGawel, DanutaGustafsson, MikaMattson, LinaRundquist, OlofZhang, HuanBenson, Mikael
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