期刊
CELL REPORTS
卷 16, 期 2, 页码 559-570出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.05.091
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资金
- Swedish Research Council
- Ake Wiberg's Foundation
- Cancerfonden
- Helmholtz Zentrum Munchen
- Technische Universitat Munchen
- Biotechnology and Biological Sciences Research Council (BBSRC)
- CEFIC
- Medical Research Council (MRC)
- Medical Research Council [MC_PC_U127574433] Funding Source: researchfish
- MRC [MC_PC_U127574433] Funding Source: UKRI
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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