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

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  • Colm E Nestor
  • Antonio Lentini
  • Cathrine Hägg Nilsson
  • Danuta R Gawel
  • Mika Gustafsson
  • Lina Mattson
  • Hui Wang
  • Olof Rundquist
  • Richard R Meehan
  • Bernward Klocke
  • Martin Seifert
  • Stefanie M Hauck
  • Helmut Laumen
  • Huan Zhang
  • Mikael Benson

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Original languageEnglish
Pages (from-to)559-70
Number of pages12
JournalCell Reports
Volume16
Issue number2
DOIs
Publication statusPublished - 12 Jul 2016

Abstract

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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