Abstract
MicroRNAs (miRNAs) are endogenous noncoding RNAs (∼22 nt) that regulate target gene expression at the post-transcriptional level in the cytoplasm. Recent discoveries of the presence of miRNAs and miRNA function-required argonaute family proteins in the cell nucleus have prompted us to hypothesize that miRNAs may also have regulatory functions in the cell nucleus. In this study, we demonstrate that mouse miR-709 is predominantly located in the nucleus of various cell types and that its nuclear localization pattern rapidly changes upon apoptotic stimuli. In the cell nucleus, miR-709 directly binds to a 19-nt miR-709 recognition element on pri-miR-15a/16-1 and prevents its processing into pre-miR-15a/16-1, leading to a suppression of miR-15a/16-1 maturation. Furthermore, nuclear miR-709 participates in the regulation of cell apoptosis through the miR-15a/16-1 pathway. In summary, the present study provides the first evidence that one miRNA can control the biogenesis of other miRNAs by directly targeting their primary transcripts in the nucleus.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (30871019, 30890044 and 30988003) and the National Basic Research Program of China (2007CB815804 and 2011CB504803863).
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
Supplementary information
Supplementary information, Figure S1
Assess purity and integrity of nucleus fraction (PDF 83 kb)
Supplementary information, Figure S2
The expression profile of miR-709 through different tissues in C57BL/6J mice. (PDF 91 kb)
Supplementary information, Figure S3
Exogenous miR-709 precursor or antisense impact miR-709 nucleus fraction both in mouse and human. (PDF 98 kb)
Supplementary information, Figure S4
Screening for the target miRNAs of miR-709 in the nucleus via microarray assay (only top 44 miRNAs were showed). (PDF 129 kb)
Supplementary information, Figure S5
The correlation between nuclear miR-709 and pri-miR-15a/16-1 processing efficiency in mice (seven tissues including testis, brain, spleen, thymus, kidney, heart, and lung). (PDF 78 kb)
Supplementary information, Figure S6
Serum starvation (SS) induced apoptotic responses in L929 cells. (PDF 94 kb)
Supplementary information, Figure S7
TNF-α induced apoptotic responses in L929 cells. (PDF 86 kb)
Supplementary information, Figure S8
Predicted various target for miR-709 in mouse. (PDF 162 kb)
Supplementary information, Figure S9
A model for the miRNA hierarchy system. (PDF 73 kb)
Supplementary information, Table S1
Liver nucleus miRNA expression profile (top 44) validated via RT-qPCR. (PDF 147 kb)
Supplementary information, Table S2
The predicted miR-709 targets in mouse miRNAs. (PDF 103 kb)
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Tang, R., Li, L., Zhu, D. et al. Mouse miRNA-709 directly regulates miRNA-15a/16-1 biogenesis at the posttranscriptional level in the nucleus: evidence for a microRNA hierarchy system. Cell Res 22, 504–515 (2012). https://doi.org/10.1038/cr.2011.137
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DOI: https://doi.org/10.1038/cr.2011.137
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