title: Alternative splicing networks regulated by signaling in human T cells.
abstract: The formation and execution of a productive immune response requires the maturation of competent T cells and a robust change in cellular activity upon antigen challenge. Such changes in cellular function depend on regulated alterations to protein expression. Previous research has focused on defining transcriptional changes that regulate protein expression during T-cell maturation and antigen stimulation. Here, we globally analyze another critical process in gene regulation during T-cell stimulation, alternative splicing. Specifically, we use RNA-seq profiling to identify 178 exons in 168 genes that exhibit robust changes in inclusion in response to stimulation of a human T-cell line. Supporting an important role for the global coordination of alternative splicing following T-cell stimulation, these signal-responsive exons are significantly enriched in genes with functional annotations specifically related to immune response. The vast majority of these genes also exhibit differential alternative splicing between naive and activated primary T cells. Comparison of the responsiveness of splicing to various stimuli in the cultured and primary T cells further reveals at least three distinct networks of signal-induced alternative splicing events. Importantly, we find that each regulatory network is specifically associated with distinct sequence features, suggesting that they are controlled by independent regulatory mechanisms. These results thus provide a basis for elucidating mechanisms of signal pathway-specific regulation of alternative splicing during T-cell stimulation.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6059, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Martinez
authors.forename: Qun
authors.initials: Q
authors.lastname: Pan
authors.forename: Brian S
authors.initials: BS
authors.lastname: Cole
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Yarosh
authors.forename: Grace A
authors.initials: GA
authors.lastname: Babcock
authors.forename: Florian
authors.initials: F
authors.lastname: Heyd
authors.forename: William
authors.initials: W
authors.lastname: Zhu
authors.forename: Sandya
authors.initials: S
authors.lastname: Ajith
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.forename: Kristen W
authors.initials: KW
authors.lastname: Lynch
mesh_terms: D017398:Alternative Splicing; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D005091:Exons; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D059372:Nucleotide Motifs; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell