title: CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus.
abstract: The transcription factor ThPOK is necessary and sufficient to trigger adoption of the CD4 lymphocyte fate. Here we investigate the regulation of ThPOK expression and its subsequent control of CD4+ T cell commitment. Treatment of immature thymocytes with anti-TCR (T cell receptor) showed that TCR signals were important in ThPOK induction and that the CD4+8lo stage was the likely target of the inductive TCR signal. We identified at the ThPOK locus a key distal regulatory element (DRE) that mediated its differential expression in class I- versus II-restricted CD4+8lo thymocytes. The DRE was both necessary for suppression of ThPOK expression in class I-restricted thymocytes and sufficient for its induction in class II-restricted thymocytes. Mutagenesis analysis defined an essential 80bp core DRE sequence and its potential regulatory motifs. We propose a silencer-dependent model of lineage choice, whereby inactivation of the DRE silencer by a strong TCR signal leads to CD4 commitment, whereas continued silencer activity leads to CD8 commitment.
authors.affiliation: Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.forename: Kyewon
authors.initials: K
authors.lastname: Park
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiang
authors.initials: X
authors.lastname: Hua
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Dietmar J
authors.initials: DJ
authors.lastname: Kappes
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics* / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037941:Silencer Elements, Transcriptional / Q000235:genetics* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology
chemical_list: D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C497211:Zbtb7b protein, mouse