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.
CITATION STYLE
Nestor, C. E., Lentini, A., Hägg Nilsson, C., Gawel, D. R., Gustafsson, M., Mattson, L., … Benson, M. (2016). 5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4+ T Cells. Cell Reports, 16(2), 559–570. https://doi.org/10.1016/j.celrep.2016.05.091
Mendeley helps you to discover research relevant for your work.