Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- And tissue-specific microRNAs

Eric Londina, Phillipe Lohera, Aristeidis G. Telonis, Kevin Quann, Peter Clark, Yi Jinga, Eleftheria Hatzimichael, Yohei Kirino, Shozo Honda, Michelle Lally, Bharat Ramratnam, Clay E S Comstock, Karen E. Knudsen, Leonard Gomella, George L. Spaeth, Lisa Hark, L. Jay Katz, Agnieszka Witkiewicz, Abdolmohamad Rostami, Sergio A. JimenezMichael A. Hollingsworth, Jen Jen Yeh, Chad A. Shaw, Steven E. McKenzie, Paul Bray, Peter T. Nelson, Simona Zupo, Katrien Van Roosbroeck, Michael J. Keating, Georg A. Calin, Charles Yeo, Masaya Jimbo, Joseph Cozzitorto, Jonathan R. Brody, Kathleen Delgrosso, John S. Mattick, Paolo Fortina, Isidore Rigoutsos

Research output: Contribution to journalArticle

244 Scopus citations

Abstract

Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ?0.05arising from3,494novel precursors; 91.5%of these novelmiRNAswere identified independently in 10 or more of the processed samples. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons. Of these novelmiRNAs, 1,657 (45%)were identified in43datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the13 tissues, indicating that thesemiRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stemloop PCR of a random collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence. Among the newly identified miRNAs are many novel miRNA clusters, new members of known miRNA clusters, previously unreported products from uncharacterized arms of miRNA precursors, and previously unrecognized paralogues of functionally important miRNA families (e.g., miR-15/107). Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7% of the newly discovered miRNAs to be human-specific whereas the majority (94.4%) are primate lineage-specific. Our findings suggest that the repertoire of human miRNAs is far more extensive than currently representedbypublic repositoriesandthat thereisasignificantnumber of lineage- and/or tissue-specific miRNAs that are uncharacterized.

Original languageEnglish (US)
Pages (from-to)E1106-E1115
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number10
DOIs
StatePublished - Mar 10 2015

Keywords

  • IsomIRs
  • MicroRNAs
  • Noncoding RNA
  • RNA sequencing
  • Transcriptome

ASJC Scopus subject areas

  • General

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    Londina, E., Lohera, P., Telonis, A. G., Quann, K., Clark, P., Jinga, Y., Hatzimichael, E., Kirino, Y., Honda, S., Lally, M., Ramratnam, B., Comstock, C. E. S., Knudsen, K. E., Gomella, L., Spaeth, G. L., Hark, L., Katz, L. J., Witkiewicz, A., Rostami, A., ... Rigoutsos, I. (2015). Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- And tissue-specific microRNAs. Proceedings of the National Academy of Sciences of the United States of America, 112(10), E1106-E1115. https://doi.org/10.1073/pnas.1420955112