Analysis of nearly one thousand mammalian mirtrons reveals novel features of Dicer substrates Journal Article

Authors: Wen, J.; Ladewig, E.; Shenker, S.; Mohammed, J.; Lai, E. C.
Article Title: Analysis of nearly one thousand mammalian mirtrons reveals novel features of Dicer substrates
Abstract: Mirtrons are microRNA (miRNA) substrates that utilize the splicing machinery to bypass the necessity of Drosha cleavage for their biogenesis. Expanding our recent efforts for mammalian mirtron annotation, we use meta-analysis of aggregate datasets to identify ~500 novel mouse and human introns that confidently generate diced small RNA duplexes. These comprise nearly 1000 total loci distributed in four splicing-mediated biogenesis subclasses, with 5'-tailed mirtrons as, by far, the dominant subtype. Thus, mirtrons surprisingly comprise a substantial fraction of endogenous Dicer substrates in mammalian genomes. Although mirtron-derived small RNAs exhibit overall expression correlation with their host mRNAs, we observe a subset with substantial differences that suggest regulated processing or accumulation. We identify characteristic sequence, length, and structural features of mirtron loci that distinguish them from bulk introns, and find that mirtrons preferentially emerge from genes with larger numbers of introns. While mirtrons generate miRNA-class regulatory RNAs, we also find that mirtrons exhibit many features that distinguish them from canonical miRNAs. We observe that conventional mirtron hairpins are substantially longer than Drosha-generated pre-miRNAs, indicating that the characteristic length of canonical pre-miRNAs is not a general feature of Dicer substrate hairpins. In addition, mammalian mirtrons exhibit unique patterns of ordered 5' and 3' heterogeneity, which reveal hidden complexity in miRNA processing pathways. These include broad 3'-uridylation of mirtron hairpins, atypically heterogeneous 5' termini that may result from exonucleolytic processing, and occasionally robust decapitation of the 5' guanine (G) of mirtron-5p species defined by splicing. Altogether, this study reveals that this extensive class of non-canonical miRNA bears a multitude of characteristic properties, many of which raise general mechanistic questions regarding the processing of endogenous hairpin transcripts. © 2015 Wen et al.
Keywords: controlled study; unclassified drug; nonhuman; molecular genetics; genetic analysis; mouse; microrna; gene expression; molecular dynamics; gene locus; intron; enzyme substrate; structure activity relation; dna modification; molecular evolution; messenger rna; genomics; dna flanking region; untranslated rna; rna processing; enzyme substrate complex; bioaccumulation; protein cleavage; rna splicing; biogenesis; genetic heterogeneity; dicer; rna sequence; genetic parameters; genetic regulation; uridylation; mirtron; human; article; microrna 1236; microrna 4745; microrna 5132; microrna 6753; gene intron number
Journal Title: PLoS Computational Biology
Volume: 11
Issue: 9
ISSN: 1553-7358
Publisher: Public Library of Science  
Date Published: 2015-09-01
Start Page: e1004441
Language: English
DOI: 10.1371/journal.pcbi.1004441
PROVIDER: scopus
PMCID: PMC4556696
PUBMED: 26325366
Notes: Export Date: 2 November 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Eric C Lai
    135 Lai
  2. Jiayu Wen
    11 Wen
  3. Erik Manfred Ladewig
    14 Ladewig