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 M, Huh JR, Day K, Issuree PD, Galan C, Gobeil S, Absher D, Green MR, Littman DR. (2015). Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages. Molecular, Cell and Cancer Biology Publications. https://doi.org/10.1038/ni.3198. Retrieved from https://escholarship.umassmed.edu/mccb_pubs/29