title: TRIM28 mediates chromatin modifications at the TCRα enhancer and regulates the development of T and natural killer T cells.
abstract: T-cell receptor-α (TCRα) rearrangement in CD4(+)CD8(+) double-positive immature thymocytes is a prerequisite for production of αβ T cells and invariant natural killer T cells. This developmental event is regulated by the TCRα enhancer (Eα), which induces chromatin modification and recruitment of the recombination-activating proteins Rag1 and Rag2. However, the molecular mechanism underlying the activation and long-range action of Eα remains incompletely understood. We show here that the chromatin-modifying factor TRIM28 is highly expressed in double-positive thymocytes and persistently phosphorylated at serine 473. TRIM28 binds to Eα and induces histone 3 lysine 4 trimethylation in the Eα and distant regions of the TCRα locus, coupled with recruitment of Rag proteins. T-cell-conditional ablation of TRIM28 impaired TCRα gene rearrangement and compromised the development of αβ T cells and invariant natural killer T cells. These findings establish TRIM28 as a unique regulator of thymocyte development and highlight an epigenetic mechanism involving TRIM28-mediated active chromatin modification in the TCRα locus.
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhou
authors.forename: Jiayi
authors.initials: J
authors.lastname: Yu
authors.forename: Mikyoung
authors.initials: M
authors.lastname: Chang
authors.forename: Minying
authors.initials: M
authors.lastname: Zhang
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhou
authors.forename: Florence
authors.initials: F
authors.lastname: Cammas
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000276:immunology; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D060168:Thymocytes / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D006657:Histones; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D012097:Repressor Proteins; C064658:RAG-1 protein; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28