title: Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages.
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.
authors.affiliation: 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.
authors.forename: MacLean
authors.initials: M
authors.lastname: Sellars
authors.affiliation: 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.
authors.forename: Jun R
authors.initials: JR
authors.lastname: Huh
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Day
authors.affiliation: 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.
authors.forename: Priya D
authors.initials: PD
authors.lastname: Issuree
authors.affiliation: 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.
authors.forename: Carolina
authors.initials: C
authors.lastname: Galan
authors.affiliation: 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.
authors.forename: Stephane
authors.initials: S
authors.lastname: Gobeil
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.affiliation: 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.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.affiliation: 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.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation / Q000276:immunology*; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D018345:Mice, Knockout; D008822:Mice, Transgenic; D034622:RNA Interference / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D002843:Chromatin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D014157:Transcription Factors; C497211:Zbtb7b protein, mouse