Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages
Department of Molecular, Cell and Cancer Biology
Animals; Antigens, CD4; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Lineage; Cells, Cultured; Chromatin; DNA (Cytosine-5-)-Methyltransferase; DNA Methylation; Flow Cytometry; Gene Expression; HEK293 Cells; Humans; Mice, Knockout; Mice, Transgenic; RNA Interference; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer; Transcription Factors
Cell Biology | Developmental Biology | Genetics | Immunity | Molecular Biology | Molecular Genetics
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.
DOI of Published Version
Nat Immunol. 2015 Jul;16(7):746-54. doi: 10.1038/ni.3198. Epub 2015 Jun 1. Link to article on publisher's site
Sellars, MacLean; Huh, Jun R.; Day, Kenneth; Issuree, Priya D.; Galan, Carolina; Gobeil, Stephane; Absher, Devin; Green, Michael R.; and Littman, Dan R., "Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages" (2015). Molecular, Cell and Cancer Biology Publications. 29.