title: Repression of Ccr9 transcription in mouse T lymphocyte progenitors by the Notch signaling pathway.
abstract: The chemokine receptor CCR9 controls the immigration of multipotent hematopoietic progenitor cells into the thymus to sustain T cell development. Postimmigration, thymocytes downregulate CCR9 and migrate toward the subcapsular zone where they recombine their TCR β-chain and γ-chain gene loci. CCR9 is subsequently upregulated and participates in the localization of thymocytes during their selection for self-tolerant receptor specificities. Although the dynamic regulation of CCR9 is essential for early T cell development, the mechanisms controlling CCR9 expression have not been determined. In this article, we show that key regulators of T cell development, Notch1 and the E protein transcription factors E2A and HEB, coordinately control the expression of Ccr9. E2A and HEB bind at two putative enhancers upstream of Ccr9 and positively regulate CCR9 expression at multiple stages of T cell development. In contrast, the canonical Notch signaling pathway prevents the recruitment of p300 to the putative Ccr9 enhancers, resulting in decreased acetylation of histone H3 and a failure to recruit RNA polymerase II to the Ccr9 promoter. Although Notch signaling modestly modulates the binding of E proteins to one of the two Ccr9 enhancers, we found that Notch signaling represses Ccr9 in T cell lymphoma lines in which Ccr9 transcription is independent of E protein function. Our data support the hypothesis that activation of Notch1 has a dominant-negative effect on Ccr9 transcription and that Notch1 and E proteins control the dynamic expression of Ccr9 during T cell development.
authors.affiliation: Committee on Molecular Pathogenesis and Molecular Medicine, The University of Chicago, Chicago, IL 60637;
authors.forename: Veena
authors.initials: V
authors.lastname: Krishnamoorthy
authors.affiliation: Committee on Immunology, The University of Chicago, Chicago, IL 60637;
authors.forename: Tiffany
authors.initials: T
authors.lastname: Carr
authors.affiliation: Committee on Immunology, The University of Chicago, Chicago, IL 60637;
authors.forename: Renee F
authors.initials: RF
authors.lastname: de Pooter
authors.forename: Akinola Olumide
authors.initials: AO
authors.lastname: Emanuelle
authors.affiliation: Committee on Immunology, The University of Chicago, Chicago, IL 60637;
authors.forename: Emanuelle Olumide
authors.initials: EO
authors.lastname: Akinola
authors.affiliation: Committee on Immunology, The University of Chicago, Chicago, IL 60637; Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL 60637; and.
authors.forename: Fotini
authors.initials: F
authors.lastname: Gounari
authors.affiliation: Committee on Molecular Pathogenesis and Molecular Medicine, The University of Chicago, Chicago, IL 60637; Committee on Immunology, The University of Chicago, Chicago, IL 60637; Department of Pathology, The University of Chicago, Chicago, IL 60637 bkee@bsd.uchicago.edu.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Kee
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016130:Immunophenotyping; D054503:Lymphoid Progenitor Cells / Q000378:metabolism*; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054388:Receptors, CCR / Q000235:genetics*; D051880:Receptors, Notch; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; C119309:CC chemokine receptor 9; D012333:RNA, Messenger; D054388:Receptors, CCR; D051880:Receptors, Notch; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors