Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages

MacLean Sellars; Jun R Huh; Kenneth Day; Priya D Issuree; Carolina Galan; Stephane Gobeil; Devin Absher; Michael R Green; Dan R Littman

doi:10.1038/ni.3198

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Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages

Journal article

Peer reviewed

Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages

MacLean Sellars, Jun R Huh, Kenneth Day, Priya D Issuree, Carolina Galan, Stephane Gobeil, Devin Absher, Michael R Green and Dan R Littman

Nature immunology, Vol.16(7), pp.746-754

07/2015

DOI: 10.1038/ni.3198

PMCID: PMC4474743

PMID: 26030024

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Abstract

During development, progenitor cells with binary potential give rise to daughter cells that have distinct functions. Heritable epigenetic mechanisms then lock in gene-expression programs that define lineage identity. Regulation of the gene encoding the T cell-specific coreceptor CD4 in helper and cytotoxic T cells exemplifies this process, with enhancer- and silencer-regulated establishment of epigenetic memory for stable gene expression and repression, respectively. Using a genetic screen, we identified the DNA-methylation machinery as essential for maintaining silencing of Cd4 in the cytotoxic lineage. Furthermore, we found a requirement for the proximal enhancer in mediating the removal of DNA-methylation marks from Cd4, which allowed stable expression of Cd4 in helper T cells. Our findings suggest that stage-specific methylation and demethylation events in Cd4 regulate its heritable expression in response to the distinct signals that dictate lineage 'choice' during T cell development.

Animals

CD4 Antigens - genetics

CD4 Antigens - immunology

CD4 Antigens - metabolism

CD4-Positive T-Lymphocytes - immunology

CD4-Positive T-Lymphocytes - metabolism

CD8-Positive T-Lymphocytes - immunology

CD8-Positive T-Lymphocytes - metabolism

Cell Differentiation - genetics

Cell Differentiation - immunology

Cell Lineage - genetics

Cell Lineage - immunology

Cells, Cultured

Chromatin - genetics

Chromatin - immunology

Chromatin - metabolism

DNA (Cytosine-5-)-Methyltransferase 1

DNA (Cytosine-5-)-Methyltransferases - genetics

DNA (Cytosine-5-)-Methyltransferases - immunology

DNA (Cytosine-5-)-Methyltransferases - metabolism

DNA Methylation - immunology

Flow Cytometry

Gene Expression - immunology

HEK293 Cells

Humans

Mice, Knockout

Mice, Transgenic

RNA Interference - immunology

T-Lymphocytes, Cytotoxic - immunology

T-Lymphocytes, Cytotoxic - metabolism

T-Lymphocytes, Helper-Inducer - immunology

T-Lymphocytes, Helper-Inducer - metabolism

Transcription Factors - genetics

Transcription Factors - immunology

Transcription Factors - metabolism

Details

Title: Subtitle: Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages
Creators: MacLean Sellars - New York University
Jun R Huh - New York University
Kenneth Day - HudsonAlpha Institute for Biotechnology
Priya D Issuree - New York University
Carolina Galan - New York University
Stephane Gobeil - University of Massachusetts Chan Medical School
Devin Absher - HudsonAlpha Institute for Biotechnology
Michael R Green - University of Massachusetts Chan Medical School
Dan R Littman - New York University
Resource Type: Journal article
Publication Details: Nature immunology, Vol.16(7), pp.746-754
DOI: 10.1038/ni.3198
PMID: 26030024
PMCID: PMC4474743
NLM abbreviation: Nat Immunol
ISSN: 1529-2908
eISSN: 1529-2916
Grant note: K99 DK091508 / NIDDK NIH HHS GM033977 / NIGMS NIH HHS T32 CA009161 / NCI NIH HHS R00 DK091508 / NIDDK NIH HHS Howard Hughes Medical Institute R01 GM033977 / NIGMS NIH HHS 5 T32 CA009161-36 / NCI NIH HHS R00DK091508 / NIDDK NIH HHS
Language: English
Date published: 07/2015
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984359870502771

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