title: Myosin VI regulates gene pairing and transcriptional pause release in T cells.
abstract: Naive CD4 T cells differentiate into several effector lineages, which generate a stronger and more rapid response to previously encountered immunological challenges. Although effector function is a key feature of adaptive immunity, the molecular basis of this process is poorly understood. Here, we investigated the spatiotemporal regulation of cytokine gene expression in resting and restimulated effector T helper 1 (Th1) cells. We found that the Lymphotoxin (LT)/TNF alleles, which encode TNF-α, were closely juxtaposed shortly after T-cell receptor (TCR) engagement, when transcription factors are limiting. Allelic pairing required a nuclear myosin, myosin VI, which is rapidly recruited to the LT/TNF locus upon restimulation. Furthermore, transcription was paused at the TNF locus and other related genes in resting Th1 cells and released in a myosin VI-dependent manner following activation. We propose that homologous pairing and myosin VI-mediated transcriptional pause release account for the rapid and efficient expression of genes induced by an external stimulus.
authors.affiliation: Departments of Immunobiology and Genetics, and.
authors.forename: Cornelia E
authors.initials: CE
authors.lastname: Zorca
authors.affiliation: Departments of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Lark Kyun
authors.initials: LK
authors.lastname: Kim
authors.affiliation: Genetics, and.
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada; and.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Krause
authors.affiliation: Département de Biochimie, Université de Montréal, Montreal, QC H3T 1J4, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zenklusen
authors.affiliation: Departments of Immunobiology and.
authors.forename: Charalampos G
authors.initials: CG
authors.lastname: Spilianakis
authors.affiliation: Departments of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520; richard.flavell@yale.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000483:Alleles; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D008233:Lymphotoxin-alpha / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018995:Myosin Heavy Chains / Q000235:genetics / Q000502:physiology*; D012319:RNA Polymerase II / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; D008233:Lymphotoxin-alpha; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; C089785:myosin VI; D012319:RNA Polymerase II; D018995:Myosin Heavy Chains
keywords: GRO-seq; homolog pairing; myosin VI; polymerase pausing