title: Characterization of the mammalian miRNA turnover landscape.
abstract: Steady state cellular microRNA (miRNA) levels represent the balance between miRNA biogenesis and turnover. The kinetics and sequence determinants of mammalian miRNA turnover during and after miRNA maturation are not fully understood. Through a large-scale study on mammalian miRNA turnover, we report the co-existence of multiple cellular miRNA pools with distinct turnover kinetics and biogenesis properties and reveal previously unrecognized sequence features for fast turnover miRNAs. We measured miRNA turnover rates in eight mammalian cell types with a combination of expression profiling and deep sequencing. While most miRNAs are stable, a subset of miRNAs, mostly miRNA*s, turnovers quickly, many of which display a two-step turnover kinetics. Moreover, different sequence isoforms of the same miRNA can possess vastly different turnover rates. Fast turnover miRNA isoforms are enriched for 5' nucleotide bias against Argonaute-(AGO)-loading, but also additional 3' and central sequence features. Modeling based on two fast turnover miRNA*s miR-222-5p and miR-125b-1-3p, we unexpectedly found that while both miRNA*s are associated with AGO, they strongly differ in HSP90 association and sensitivity to HSP90 inhibition. Our data characterize the landscape of genome-wide miRNA turnover in cultured mammalian cells and reveal differential HSP90 requirements for different miRNA*s. Our findings also implicate rules for designing stable small RNAs, such as siRNAs.
authors: Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA Yale Stem Cell Center, Yale Cancer Center, New Haven, CT 06520, USA Graduate Program in Biological and Biomedical Sciences, Yale University, New Haven, CT 06510, USA.
authors: Yanwen
authors: Y
authors: Guo
authors: Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA Yale Stem Cell Center, Yale Cancer Center, New Haven, CT 06520, USA.
authors: Jun
authors: J
authors: Liu
authors: Yale Stem Cell Center, Yale Cancer Center, New Haven, CT 06520, USA Computational Biology and Bioinformatics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Sarah J
authors: SJ
authors: Elfenbein
authors: Yale Stem Cell Center, Yale Cancer Center, New Haven, CT 06520, USA.
authors: Yinghong
authors: Y
authors: Ma
authors: Yale Stem Cell Center, Yale Cancer Center, New Haven, CT 06520, USA.
authors: Mei
authors: M
authors: Zhong
authors: Yale Stem Cell Center, Yale Cancer Center, New Haven, CT 06520, USA.
authors: Caihong
authors: C
authors: Qiu
authors: Wadsworth Center, New York State Department of Health, Albany, NY 12208, USA.
authors: Ye
authors: Y
authors: Ding
authors: Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA Yale Stem Cell Center, Yale Cancer Center, New Haven, CT 06520, USA Yale Center for RNA Science and Medicine, New Haven, CT 06520, USA jun.lu@yale.edu.
authors: Jun
authors: J
authors: Lu
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D059368:RNA Isoforms / Q000378:metabolism; D020871:RNA Stability; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D060565:Argonaute Proteins; D018841:HSP90 Heat-Shock Proteins; D035683:MicroRNAs; D019384:Nucleic Acid Synthesis Inhibitors; D059368:RNA Isoforms
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