title: Intronic splicing enhancers, cognate splicing factors and context-dependent regulation rules.
abstract: Most human genes produce multiple splicing isoforms with distinct functions. To systematically understand splicing regulation, we conducted an unbiased screen and identified >100 intronic splicing enhancers (ISEs), clustered by sequence similarity. All ISEs functioned in multiple cell types and in heterologous introns, and patterns of distribution and conservation across pre-mRNA regions were similar to those of exonic splicing silencers. Consistently, all ISEs inhibited use of splice sites from exons. Putative trans-factors of each ISE group were identified and validated. Five distinct groups were recognized by hnRNP H and hnRNP F, whose C-terminal domains were sufficient to render context-dependent activities of ISEs. The sixth group was controlled by factors that either activate or suppress splicing. We provide a comprehensive picture of general ISE activities and suggest new models of how single elements can function oppositely, depending on locations and binding factors.
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Meng
authors.initials: M
authors.lastname: Ma
authors.forename: Xinshu
authors.initials: X
authors.lastname: Xiao
authors.forename: Zefeng
authors.initials: Z
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007438:Introns; D059372:Nucleotide Motifs; D017434:Protein Structure, Tertiary; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: C412481:DAZAP1 protein, human; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; C473692:RBM4 protein, human; D012322:RNA Precursors; D016601:RNA-Binding Proteins