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5-hydroxymethylcytosine remodeling precedes lineage specification during differentiation of human CD4+ T cells.

Cell Rep. 16, 559-570 (2016)
Publishers Version DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
as soon as is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hematopoietic Stem-cells; Dna Methylation; Autoimmune-disease; Enhancer Activity; Wide Association; Gene-expression; Risk Loci; Tet2; State; 5-methylcytosine
Reviewing status
Institute(s) Research Unit Protein Science (PROT)
CCG Nutrigenomics and Type 2 Diabetes (KKG-KDN)