title: Cascading suppression of transcriptional silencers by ThPOK seals helper T cell fate.
abstract: CD4 and the transcription factor ThPOK are essential for the differentiation of major histocompatibility complex class II-restricted thymocytes into the helper T cell lineage; their genes (Cd4 and Zbtb7b (called 'ThPOK' here)) are repressed by transcriptional silencer elements in cytotoxic T cells. The molecular mechanisms regulating expression of these genes during helper T cell lineage differentiation remain unknown. Here we showed that inefficient upregulation of ThPOK, induced by removal of the proximal enhancer from the ThPOK locus, resulted in the transdifferentiation of helper lineage-specified cells into the cytotoxic T cell lineage. Furthermore, direct antagonism by ThPOK of the Cd4 and ThPOK silencers generated two regulatory loops that initially inhibited Cd4 downregulation and later stabilized ThPOK expression. Our results show how an initial lineage-specification signal can be amplified and stabilized during the lineage-commitment process.
authors.affiliation: Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Muroi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Naoe
authors.forename: Chizuko
authors.initials: C
authors.lastname: Miyamoto
authors.forename: Kaori
authors.initials: K
authors.lastname: Akiyama
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Ikawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Masuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Taniuchi
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D054338:Cell Transdifferentiation / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D037941:Silencer Elements, Transcriptional / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D014157:Transcription Factors; C497211:Zbtb7b protein, mouse