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An integrated expression atlas of miRNAs and their promoters in human and mouse

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs with key roles in cellular regulation. As part of the fifth edition of the Functional Annotation of Mammalian Genome (FANTOM5) project, we created an integrated expression atlas of miRNAs and their promoters by deep-sequencing 492 short RNA (sRNA) libraries, with matching Cap Analysis Gene Expression (CAGE) data, from 396 human and 47 mouse RNA samples. Promoters were identified for 1,357 human and 804 mouse miRNAs and showed strong sequence conservation between species. We also found that primary and mature miRNA expression levels were correlated, allowing us to use the primary miRNA measurements as a proxy for mature miRNA levels in a total of 1,829 human and 1,029 mouse CAGE libraries. We thus provide a broad atlas of miRNA expression and promoters in primary mammalian cells, establishing a foundation for detailed analysis of miRNA expression patterns and transcriptional control regions.

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Figure 1: Selection of robust miRNAs and Drosha CAGE peak analysis.
Figure 2: Expression profile and cell ontology analysis of mature miRNAs.
Figure 3: Analysis of the curated miRNA promoters of miRNAs in the robust set.

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DDBJ/GenBank/EMBL

Gene Expression Omnibus

Referenced accessions

DDBJ/GenBank/EMBL

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Acknowledgements

FANTOM5 was made possible by the following grants: Research Grant for RIKEN Omics Science Center from MEXT to Y.H.; Grant of the Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from the MEXT to Y.H.; Research Grant from MEXT to the RIKEN Center for Life Science Technologies; Research Grant to RIKEN Preventive Medicine and Diagnosis Innovation Program from MEXT to Y.H. K.V.-S. and A.S. were supported by the Lundbeck and Novo Nordisk Foundations. A.R.R.F. is supported by a Senior Cancer Research Fellowship from the Cancer Research Trust, funds raised by the MACA Ride to Conquer Cancer, and the Australian Research Council's Discovery Projects funding scheme (DP160101960). Y.A.M. was supported by the Russian Science Foundation, grant 15-14-30002. R.D. was supported by the Russian Science Foundation, grant 14-44-00022. We would like to thank L. Schwarzfischer for technical assistance and N. Eichner and G. Meister for sequencing RACE products. We would also like to thank GeNAS for data production.

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P.A., G.Å., M.B., A.J.C., M.D., D.G., S.G., T.J.H., M.H., P.H., K.J.H., C.K., P.K., W.L., N.M., M.O., M.O.-H., P.R., H.S., R.K.S., H.To., M.Y., N.Y., S.Z., P.G.Z., L.W., Y.Y., C.A.W., K.M.S., and A.R.R.F. provided RNA samples; E.A. and C.O.D. selected samples from the FANTOM5 time courses; Y.I., S.N., and H.Ta. produced the sRNA libraries; I.A., M.L., H.K., and T.K. managed the data; D.d.R., M.J.L.d.H., K.V.-S., A.M.B., T.A., H.A., A.H., T.L., H.P., C.-H.L. A.M., V.M., and M.R. carried out the bioinformatics analyses with the help of C.C.H., M.L., K.H., F.R., and J.S.; C.J.M. provided the cell ontology; K.M.S. created the Miru visualization; A.F., A.M., A.R.R.F., A.S., C.-H.L. C.A.W., D.d.R., E.H., F.R., H.P., K.V.-S., A.M.B., M.J.L.d.H., M.R., N.B., P.S., R.D., V.M., and Y.A.M. contributed to the manual miRNA promoter annotation; K.Y. and J.W.S. performed the expression validation experiments of known miRNAs; E.H. and C.A.W. performed the validation experiments of candidate miRNAs; C.G. and M.R. performed the RACE experiments; J.H. created the web visualization tool; D.d.R., A.R.R.F., and M.J.L.d.H. wrote the manuscript with the help of E.A., A.S., A.M.B., K.M.S., K.V.-S., M.R., N.B., P.C., P.S., and C.A.W.; A.R.R.F. and M.J.L.d.H. designed the study; P.C. and Y.H. supervised the FANTOM5 project.

Corresponding authors

Correspondence to Alistair R R Forrest or Michiel J L de Hoon.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–29 and Supplementary Note (PDF 3223 kb)

Life Sciences Reporting Summary (PDF 158 kb)

Supplementary Table 1

Short RNA data sets analyzed in this study. (XLSX 37 kb)

Supplementary Table 2

Novel RNA samples used. Most FANTOM5 human and mouse RNA samples used were described previously (ref. 17,18) and are therefore not included in this table. (XLSX 55 kb)

Supplementary Table 3

FANTOM5 RNA samples and sRNA libraries. Matching CAGE (ref. 17–19) and sRNA libraries were produced from the same RNA sample. In total, five of the CAGE libraries and two of the sRNA libraries were discarded because of their low quality; for one of the RNA samples, an sRNA library but no CAGE library was produced. (XLSX 38 kb)

Supplementary Table 4

Evaluation of human pre-miRNAs. For each pre-miRNA in the human robust, permissive, and candidate set, we evaluated the miRBase high-confidence criteria (Table 2), and the statistical significance of the Drosha CAGE peak as observed in the FANTOM5 and ENCODE CAGE data. (XLSX 463 kb)

Supplementary Table 5

Evaluation of murine pre-miRNAs. For each pre-miRNA in the murine robust, permissive, and candidate set, we evaluated the miRBase high-confidence criteria (Table 2), and the statistical significance of the Drosha CAGE peak as observed in the FANTOM5 CAGE data. (XLSX 161 kb)

Supplementary Table 6

Genomic locations of the candidate miRNAs predicted by miRDeep2 in human (genome assembly hg19). (XLSX 764 kb)

Supplementary Table 7

Genome sequence at the genomic locus of each candidate miRNA in human, the secondary structure of the predicted pre-miRNA with the corresponding ΔG, and aligning reads with their counts. Sequenced nucleotides that do not match the genome sequence are shown in lowercase. (XLSX 2535 kb)

Supplementary Table 8

Genomic locations of the candidate miRNAs predicted by miRDeep2 in mouse (genome assembly mm9). (XLSX 215 kb)

Supplementary Table 9

Genome sequence at the genomic locus of each candidate miRNA in mouse, the secondary structure of the predicted pre-miRNA with the corresponding ΔG, and aligning reads with their counts. Sequenced nucleotides that do not match the genome sequence are shown in lowercase. (XLSX 704 kb)

Supplementary Table 10

Forward primers used for the validation of candidate miRNA expression by qPCR. (XLSX 41 kb)

Supplementary Table 11

Expression table of human miRNAs in the robust, permissive, and candidate set. The values shown are the (unnormalized) counts of sequence reads overlapping the mature miRNA region, and may be non-integer due to sequence reads mapping to multiple genomic locations. (XLSX 19326 kb)

Supplementary Table 12

Expression table of murine miRNAs in the robust, permissive, and candidate set. The values shown are the (unnormalized) counts of sequence reads overlapping the mature miRNA region, and may be non-integer due to sequence reads mapping to multiple genomic locations. (XLSX 1334 kb)

Supplementary Table 13

Cell ontology enrichment analysis. For each mature miRNA, we show the cell type specificity index, the median and maximum expression level, the RNA sample in which the miRNA was most highly expressed, the top-3 cell ontology clusters in which its expression is most enriched, with the corresponding significance value and the base-2 logarithm of the expression fold-ratio, and the top-3 cell ontology clusters in which its expression is most depleted, with the corresponding significance value and the base-2 logarithm of the expression fold-ratio. (XLSX 974 kb)

Supplementary Table 14

RNA samples contained in each cell ontology cluster (sRNA data). (XLSX 37 kb)

Supplementary Table 15

Computational miRNA promoter predictions in human. For each primary miRNA, we show the genomic location (chromosome, strand, and transcription start site; genome assembly hg19) and name of the predicted promoter, the corresponding primary miRNA, their status as intronic (if the primary miRNA transcript is coding) or intergenic (if the primary miRNA is non-coding), the pre-miRNAs contained in the primary miRNA, the average sequence conservation of the miRNA promoter, the maximum CAGE expression level, the RNA sample in which the primary miRNA promoter was most highly expressed, the top-3 cell ontology clusters in which CAGE expression of this promoter is most enriched, with the corresponding statistical significance and the base-2 logarithm of the expression fold-ratio, and the top-3 cell ontology clusters in which CAGE expression of this promoter is most depleted, with the corresponding statistical significance and the base-2 logarithm of the expression fold-ratio. The promoter loci and names were taken from the FANTOM5 permissive promoter set (ref. 17). (XLSX 1121 kb)

Supplementary Table 16

MicroRNA promoter predictions in mouse. For each primary miRNA, we show the genomic location (chromosome, strand, and transcription start site; genome assembly mm9) and name of the predicted promoter, the corresponding primary miRNA, their status as intronic (if the primary miRNA transcript is coding) or intergenic (if the primary miRNA is non-coding), the pre-miRNAs contained in the primary miRNA, and the average sequence conservation of the miRNA promoter. The promoter loci and names were taken from the FANTOM5 permissive promoter set (ref. 17). (XLSX 165 kb)

Supplementary Table 17

Curated miRNA promoter predictions in human. For each primary miRNA, we show the genomic location (chromosome, strand, and transcription start site; genome assembly hg19) and name of the predicted promoter, the corresponding primary miRNA, their status as intronic (if the primary miRNA transcript is coding) or intergenic (if the primary miRNA is non-coding), the pre-miRNAs contained in the primary miRNA, the average sequence conservation of the miRNA promoter, the maximum CAGE expression level, the RNA sample in which the primary miRNA promoter was most highly expressed, the top-3 cell ontology clusters in which CAGE expression of this promoter is most enriched, with the corresponding statistical significance and the base-2 logarithm of the expression fold-ratio, and the top-3 cell ontology clusters in which CAGE expression of this promoter is most depleted, with the corresponding statistical significance and the base-2 logarithm of the expression fold-ratio. The promoter loci and names were taken from the FANTOM5 permissive promoter set (ref. 17). (XLSX 1145 kb)

Supplementary Table 18

Outer and inner primers used for the validation of miRNA promoters by RACE. (XLSX 35 kb)

Supplementary Table 19

Spearman correlation across human primary cells between the mature miRNA expression, as measured by sRNA sequencing, and the miRNA promoter, as measured by CAGE. (XLSX 242 kb)

Supplementary Table 20

RNA samples contained in each cell ontology cluster (CAGE data). (XLSX 76 kb)

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de Rie, D., Abugessaisa, I., Alam, T. et al. An integrated expression atlas of miRNAs and their promoters in human and mouse. Nat Biotechnol 35, 872–878 (2017). https://doi.org/10.1038/nbt.3947

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