Evidence for the biogenesis of more than 1,000 novel human microRNAs

Friedländer, Marc R.; Lizano, Esther; Houben, Anna J.S.; Bezdan, Daniela; Báñez-Coronel, Mónica; Kudla, Grzegorz; Mateu-Huertas, Elisabet; Kagerbauer, Birgit; González, Justo; Chen, Kevin C.; LeProust, Emily; Martı́, Eulàlia; Estivill, Xavier

doi:10.1186/gb-2014-15-4-r57

Cited by 223 publications

(193 citation statements)

References 58 publications

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“…Recent analyses revealed the presence of novel tissue-specific miRNAs (33). To determine whether our identified miRNAs exhibit tissue-dependent expression, we normalized the expression level of each miRNA as previously described (44,45) and separately for each sample.…”

Section: Resultsmentioning

confidence: 99%

“…A little more than 1,800 human miRNA precursors are listed in release 20 (June 2013) of miRBase (31,32), each giving rise to one or two mature miRNA products. Recent analyses using next-generation sequencing have resulted in the identification of new human and mouse miRNAs (28,(33)(34)(35)(36)(37) and have suggested the existence of tissue-specific miRNAs (33). We reasoned that many more miRNAs are present and can be identified through the analysis of additional samples representing more diverse tissue types.…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

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

Londin

Lohera

Telonis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

370

355

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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 3,494 novel 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 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 represented by public repositories and that there is a significant number of lineage-and/or tissue-specific miRNAs that are uncharacterized. SignificanceMicroRNAs (miRNAs) are small ∼22-nt RNAs that are important regulators of posttranscriptional gene expression. Since their initial discovery, they have been shown to be involved in many cellular processes, and their misexpression is associated with disease etiology. Currently, nearly 2,800 human miRNAs are annotated in public repositories. A key question in miRNA research is how many miRNAs are harbored by the human genome. To answer this question, we examined 1,323 short RNA sequence samples and identified 3,707 novel miRNAs, many of which are human-specific and tissue-specific. Our findings suggest that the human genome expresses a greater number of miRNAs than has previously been appreciated and that many more miRNA molecules may play key roles in disease etiology.

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Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

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

Londin

Lohera

Telonis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

370

355

View full text Add to dashboard Cite

show abstract

“…miRNAs satisfied by the following criteria, the tags aligned to miRNA precursor in miRBase with no any mismatch and the tags aligned to the mature miRNA in miRBase with at least 16 nt overlap allowing offsets would be counted to get the expression of identified miRNAs. For the remained reads without any annotation, Miredp was used to predict the potential novel miRNAs and its stem loop structure based on references (Friedländer, Mackowiak, Li, Chen, & Rajewsky, 2012; Friedländer et al, 2014). To correct the biased results from low expression, miRNAs with read counts less than 5 were discarded in the differential expression analysis.…”

Section: Methodsmentioning

confidence: 99%

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Song

Sun

et al. 2018

American J of Med Genetics Pt B

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Major depression in negative mood is presumably induced by chronic stress with lack of reward. However, most individuals who experience chronic stress demonstrate resilience. Molecular mechanisms underlying stress‐ induced depression versus resilience remain unknown, which are investigated in brain reward circuits. Mice were treated by chronic unpredictable mild stress (CUMS) for 4 weeks. The tests of sucrose preference, Y‐maze, and forced swimming were used to identify depression‐like emotion behavior or resilience. High‐throughput sequencing was used to analyze mRNA and miRNA quantity in the nucleus accumbens (NAc) harvested from the mice in the groups of control, CUMS‐induced depression (CUMS‐MDD), and CUMS‐resistance to identify molecular profiles of CUMS‐MDD versus CUMS‐resilience. In data analyses and comparison among three groups, 1.5‐fold ratio in reads per kilo‐base per million reads (RPKM) was set to judge involvements of mRNA and miRNA in CUMS, MDD, or resilience. The downregulations of serotonergic/dopaminergic synapses, MAPK/calcium signaling pathways, and morphine addiction as well as the upregulations of cAMP/PI3K‐Akt signaling pathways and amino acid metabolism are associated with CUMS‐MDD. The downregulations of chemokine signaling pathway, synaptic vesicle cycle, and nicotine addiction as well as the upregulations of calcium signaling pathway and tyrosine metabolism are associated with CUMS‐resilience. The impairments of serotonergic/dopaminergic synapses and PI3K‐Akt/MAPK signaling pathways in the NAc are associated with depression. The upregulation of these entities is associated with resilience. Consistent results from analyzing mRNA/miRNA and using different methods validate our finding and conclusion.

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“…In this study we identified 1041 miRNAs altogether in the extracellular vesicle and cell samples studied, which are more than most array systems would detect. [22][23][24][25][26][27]42,43 Further, comparison among expression of miRNAs is possible with deep sequencing approaches, if the absolute number of copies in the sample can be quantified. 44 In this study, by using the Quantile normalization method for all samples, miRNA expression showed positive relationship between the samples, although many detected miRNA are unique in the different subsets of vesicles ( Fig.…”

Section: Discussionmentioning

confidence: 99%

141 Small RNA deep sequencing discriminates subsets of extracellular vesicles released by melanoma cells - evidence of unique microRNA cargos

Lunavat¹,

Lesley²,

Kim³

et al. 2015

European Journal of Cancer

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Melanoma cells release different types of extracellular vesicles (EVs) into the extracellular milieu that are involved with communication and signaling in the tumor microenvironment. Subsets of EVs include exosomes, microvesicles, and apoptotic bodies that carry protein and genetic (RNA) cargos. To define the contribution of the RNA cargo of melanoma cell derived EVs we performed small RNA sequencing to identify different small RNAs in the EV subsets. Using validated centrifugation protocols, we separated these EV subsets released by the melanoma cell line MML-1, and performed RNA sequencing with the Ion Torrent platform. Various, but different, non-coding RNAs were detected in the EV subsets, including microRNA, mitochondrial associated tRNA, small nucleolar RNA, small nuclear RNA, Ro associated Y-RNA, vault RNA and Y-RNA. We identified in total 1041 miRNAs in cells and EV subsets. Hierarchical clustering showed enrichment of specific miRNAs in exosomes, including hsa-miR-214-3p, hsa-miR-199a-3p and hsa-miR-155-5p, all being associated with melanoma progression. Comparison of exosomal miRNAs with miRNAs in clinical melanoma samples indicate that multiple miRNAs in exosomes also are expressed specifically in melanoma tissues, but not in benign naevi. This study shows for the first time the presence of distinct small RNAs in subsets of EVs released by melanoma cells, with significant similarities to clinical melanoma tissue, and provides unique insights into the contribution of EV associated extracellular RNA in cancer.

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Evidence for the biogenesis of more than 1,000 novel human microRNAs

Cited by 223 publications

References 58 publications

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

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

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

141 Small RNA deep sequencing discriminates subsets of extracellular vesicles released by melanoma cells - evidence of unique microRNA cargos

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