title: Alternative splicing regulates biogenesis of miRNAs located across exon-intron junctions.
abstract: The initial step in microRNA (miRNA) biogenesis requires processing of the precursor miRNA (pre-miRNA) from a longer primary transcript. Many pre-miRNAs originate from introns, and both a mature miRNA and a spliced RNA can be generated from the same transcription unit. We have identified a mechanism in which RNA splicing negatively regulates the processing of pre-miRNAs that overlap exon-intron junctions. Computational analysis identified dozens of such pre-miRNAs, and experimental validation demonstrated competitive interaction between the Microprocessor complex and the splicing machinery. Tissue-specific alternative splicing regulates maturation of one such miRNA, miR-412, resulting in effects on its targets that code a protein network involved in neuronal cell death processes. This mode of regulation specifically controls maturation of splice-site-overlapping pre-miRNAs but not pre-miRNAs located completely within introns or exons of the same transcript. Our data present a biological role of alternative splicing in regulation of miRNA biogenesis.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Melamed
authors.forename: Asaf
authors.initials: A
authors.lastname: Levy
authors.forename: Reut
authors.initials: R
authors.lastname: Ashwal-Fluss
authors.forename: Galit
authors.initials: G
authors.lastname: Lev-Maor
authors.forename: Keren
authors.initials: K
authors.lastname: Mekahel
authors.forename: Nir
authors.initials: N
authors.lastname: Atias
authors.forename: Shlomit
authors.initials: S
authors.lastname: Gilad
authors.forename: Roded
authors.initials: R
authors.lastname: Sharan
authors.forename: Carmit
authors.initials: C
authors.lastname: Levy
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kadener
authors.forename: Gil
authors.initials: G
authors.lastname: Ast
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D016923:Cell Death / Q000235:genetics; D005091:Exons; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007438:Introns; D055029:Inverted Repeat Sequences; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D005810:Multigene Family; D009474:Neurons / Q000502:physiology; D009690:Nucleic Acid Conformation; D011506:Proteins / Q000378:metabolism; D034622:RNA Interference; D022821:RNA Splice Sites; D016601:RNA-Binding Proteins; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism
chemical_list: C474044:Dgcr8 protein, mouse; C583335:MIRN412 microRNA, mouse; D035683:MicroRNAs; D011506:Proteins; D022821:RNA Splice Sites; D016601:RNA-Binding Proteins; C513400:Drosha protein, mouse; D043244:Ribonuclease III