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

• Published in: Cell reports (Cambridge) 2016-07, Vol.16 (2), p.559-570
• Main Authors: Nestor, Colm E., Lentini, Antonio, Hägg Nilsson, Cathrine, Gawel, Danuta R., Gustafsson, Mika, Mattson, Lina, Wang, Hui, Rundquist, Olof, Meehan, Richard R., Klocke, Bernward, Seifert, Martin, Hauck, Stefanie M., Laumen, Helmut, Zhang, Huan, Benson, Mikael
• Format: Article
• Language: English
• Subjects: 5-Methylcytosine - analogs & derivatives; 5-Methylcytosine - metabolism; CD4-Positive T-Lymphocytes - physiology; Cell Differentiation; Cell Lineage; Cells, Cultured; DNA Methylation; Gene Expression Regulation - immunology; Humans
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.05.091

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. [Display omitted] •5hmC remodeling is widespread during human CD4+ T cell differentiation•Early 5hmC gains predict loss of DNA methylation in differentiated cells•Early 5hmC remodeling in vitro predicts loss of DNA methylation in vivo•5hmC loci are enriched for functional T cell disease-associated genetic variants Nestor et al. reveal widespread 5hmC-mediated DNA de-methylation during in vitro differentiation of human CD4+ T cells. They find that regions undergoing 5hmC remodeling are enriched for disease-associated regulatory regions.