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

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

doi:10.1016/j.celrep.2016.05.091

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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	559-70
Number of pages	12
Journal	Cell Reports
Volume	16
Issue number	2
Early online date	23 Jun 2016
DOIs	https://doi.org/10.1016/j.celrep.2016.05.091
Publication status	Published - 12 Jul 2016

Access to Document

10.1016/j.celrep.2016.05.091Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

5-hydroxymethylcytosine remodeling precedes lineage _ accepted version
This is the author's final peer-reviewed manuscript as accepted for publication
Accepted author manuscript, 5.31 MB

CROATIA PROGRAMME
Wright, A. (Principal Investigator), Adams, I. (Co-investigator), Aligianis, I. (Co-investigator), Baldock, R. (Co-investigator), Bickmore, W. (Co-investigator), Caceres, J. (Co-investigator), Dorin, J. (Co-investigator), Dunlop, M. (Co-investigator), FitzPatrick, D. (Co-investigator), Haley, C. (Co-investigator), Hastie, N. (Co-investigator), Hill, B. (Co-investigator), Jackson, I. (Co-investigator), Jackson, A. (Co-investigator), Kudla, G. (Co-investigator), Meehan, R. (Co-investigator), O'Connell, M. (Co-investigator), Overton, I. (Co-investigator), Patton, E. (Co-investigator), Taylor, M. (Co-investigator), Tenesa, A. (Co-investigator) & Van Heyningen, V. (Co-investigator)
MRC
1/04/12 → 31/07/13
Project: Research

Cite this

Nestor, C. E., Lentini, A., Hägg Nilsson, C., Gawel, D. R., Gustafsson, M., Mattson, L., Wang, H., Rundquist, O., Meehan, R. R., Klocke, B., Seifert, M., Hauck, S. M., Laumen, H., Zhang, H., & Benson, M. (2016). 5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4⁺ T Cells. Cell Reports, 16(2), 559-70. https://doi.org/10.1016/j.celrep.2016.05.091

@article{786ae87bb3884c59aeb17eb22fe22012,

title = "5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4+ T Cells",

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.",

author = "Nestor, \{Colm E\} and Antonio Lentini and \{H{\"a}gg Nilsson\}, Cathrine and Gawel, \{Danuta R\} and Mika Gustafsson and Lina Mattson and Hui Wang and Olof Rundquist and Meehan, \{Richard R\} and Bernward Klocke and Martin Seifert and Hauck, \{Stefanie M\} and Helmut Laumen and Huan Zhang and Mikael Benson",

year = "2016",

month = jul,

day = "12",

doi = "10.1016/j.celrep.2016.05.091",

language = "English",

volume = "16",

pages = "559--70",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "2",

}

Nestor, CE, Lentini, A, Hägg Nilsson, C, Gawel, DR, Gustafsson, M, Mattson, L, Wang, H, Rundquist, O, Meehan, RR, Klocke, B, Seifert, M, Hauck, SM, Laumen, H, Zhang, H & Benson, M 2016, '5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4⁺ T Cells', Cell Reports, vol. 16, no. 2, pp. 559-70. https://doi.org/10.1016/j.celrep.2016.05.091

TY - JOUR

T1 - 5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4+ T Cells

AU - Nestor, Colm E

AU - Lentini, Antonio

AU - Hägg Nilsson, Cathrine

AU - Gawel, Danuta R

AU - Gustafsson, Mika

AU - Mattson, Lina

AU - Wang, Hui

AU - Rundquist, Olof

AU - Meehan, Richard R

AU - Klocke, Bernward

AU - Seifert, Martin

AU - Hauck, Stefanie M

AU - Laumen, Helmut

AU - Zhang, Huan

AU - Benson, Mikael

PY - 2016/7/12

Y1 - 2016/7/12

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2016.05.091

DO - 10.1016/j.celrep.2016.05.091

M3 - Article

C2 - 27346350

SN - 2211-1247

VL - 16

SP - 559

EP - 570

JO - Cell Reports

JF - Cell Reports

IS - 2

ER -

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

Abstract

Access to Document

Fingerprint

Projects

CROATIA PROGRAMME

Cite this

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