期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 10, 页码 E1106-E1115出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1420955112
关键词
microRNAs; isomIRs; noncoding RNA; RNA sequencing; transcriptome
资金
- William M. Keck Foundation
- Hirshberg Foundation for Pancreatic Cancer Research
- Tolz Foundation Weizmann Institute of Science-Thomas Jefferson University Collaboration Program
- NIH Autoimmune Centers of Excellence [2U19-AI056363-06/20309840]
- NIH-National Cancer Institute Core Grant [P30CA56036]
- Thomas Jefferson University Institutional funds
- NIH Grant [CA140424, AG042419, NS085830, AG028383, GM106047]
- Lifespan/Tufts/Brown Center for AIDS Research Grant [P30 AI042853]
- NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant [R01 AR 19616]
- CLL Global Research Foundation
- Sister Institution Network Foundation MD Anderson Cancer Center-German Cancer Research Center grant on Chronic Lymphocytic Leukemia
- Laura and John Arnold Foundation
- RGK Foundation
- Estate of C. G. Johnson, Jr.
- Jefferson Pancreas, Biliary and Related Cancer Center
- National Heart, Lung, and Blood Institute of the National Institutes of Health [HL102482]
- Pennsylvania Commonwealth Universal Research Enhancement grant
- Department of Defense Grant [PC094507]
- [R01 CA099996]
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 <= 0.05 arising from 3,494novel precursors; 91.5% of these novel miRNAs were 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 novel miRNAs, 1,657 (45%) were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stem-loop 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 represented by public repositories and that there is a significant number of lineage-and/or tissue-specific miRNAs that are uncharacterized.
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