title: RHS6-mediated chromosomal looping and nuclear substructure binding is required for Th2 cytokine gene expression.
abstract: Subset-specific gene expression is a critical feature of CD4 T cell differentiation. Th2 cells express Th2 cytokine genes including Il4, Il5, and Il13 and mediate the immune response against helminths. The expression of Th2 cytokine genes is regulated by Rad50 hypersensitive site 6 (RHS6) in the Th2 locus control region; however, the molecular mechanisms of RHS6 action at the chromatin level are poorly understood. Here, we demonstrate that RHS6 is crucial for chromosomal interactions and nuclear substructure binding of the Th2 cytokine locus. RHS6-deficient cells had a marked reduction in chromatin remodeling and in intrachromosomal interactions at the Th2 locus. Deficiency of RHS6-binding transcription factors GATA3, SATB1, and IRF4 also caused a great reduction in chromatin remodeling and long-range chromosomal interactions involving the Th2 locus. RHS6 deficiency abrogated association of the Th2 locus with the nuclear substructure and RNA polymerase II. Therefore, RHS6 serves as a crucial cis-acting hub for coordinate regulation of Th2 cytokine genes by forming chromosomal loops and binding to a nuclear substructure.
authors.affiliation: Department of Life Science, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea.
authors.forename: Soo Seok
authors.initials: SS
authors.lastname: Hwang
authors.affiliation: Department of Life Science, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea.
authors.forename: Sung Woong
authors.initials: SW
authors.lastname: Jang
authors.affiliation: Department of Life Science, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea. Electronic address: grlee@sogang.ac.kr.
authors.forename: Gap Ryol
authors.initials: GR
authors.lastname: Lee
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology; D017766:Acid Anhydride Hydrolases; D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000276:immunology*; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins; D019901:Locus Control Region / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
chemical_list: D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse
keywords: Chromatin remodeling; Chromosomal loop; Nuclear substructure; RHS6; Th2 locus control region