5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells
2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 2, 559-570 p.Article in journal (Refereed) Published
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.
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:liu:diva-131186DOI: 10.1016/j.celrep.2016.05.091ISI: 000380262300025PubMedID: 27346350OAI: oai:DiVA.org:liu-131186DiVA: diva2:971946
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)2016-09-192016-09-122016-10-12