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

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

Nat Immunol. 2015 Jul;16(7):746-54. doi: 10.1038/ni.3198. Epub 2015 Jun 1.

Authors

MacLean Sellars¹, Jun R Huh², Kenneth Day³, Priya D Issuree¹, Carolina Galan¹, Stephane Gobeil⁴, Devin Absher³, Michael R Green⁴, Dan R Littman¹

Affiliations

¹ 1] The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York, USA. [2] Howard Hughes Medical Institute, New York University School of Medicine, New York, New York, USA.
² 1] The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York, USA. [2] Howard Hughes Medical Institute, New York University School of Medicine, New York, New York, USA. [3] Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
³ HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
⁴ 1] Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [2] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

PMID: 26030024
PMCID: PMC4474743
DOI: 10.1038/ni.3198

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

CD4 Antigens
Chromatin
Th-POK protein, mouse
Transcription Factors
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding