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

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

Author information

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.

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.

PMID:
26030024
PMCID:
PMC4474743
DOI:
10.1038/ni.3198
[Indexed for MEDLINE]
Free PMC Article

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