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dc.contributor.authorHsu, Sheng-Daen_US
dc.contributor.authorHuang, Hsi-Yuanen_US
dc.contributor.authorChou, Chih-Hungen_US
dc.contributor.authorSun, Yi-Mingen_US
dc.contributor.authorHsu, Ming-Taen_US
dc.contributor.authorTsou, Ann-Pingen_US
dc.date.accessioned2019-04-03T06:38:15Z-
dc.date.available2019-04-03T06:38:15Z-
dc.date.issued2015-01-21en_US
dc.identifier.issn1471-2164en_US
dc.identifier.urihttp://dx.doi.org/10.1186/1471-2164-16-S2-S12en_US
dc.identifier.urihttp://hdl.handle.net/11536/124852-
dc.description.abstractBackground: MicroRNAs (miRNAs) simultaneously target many transcripts through partial complementarity binding, and have emerged as a key type of post-transcriptional regulator for gene expression. How miRNA accomplishes its pleiotropic effects largely depends on its expression and its target repertoire. Previous studies discovered thousands of miRNAs and numerous miRNA target genes mainly through computation and prediction methods which produced high rates of false positive prediction. The development of Argonaute cross-linked immunoprecipitation coupled with high-throughput sequencing (CLIP-Seq) provides a system to effectively determine miRNA target genes. Likewise, the accuracy of dissecting the transcriptional regulation of miRNA genes has been greatly improved by chromatin immunoprecipitation of the transcription factors coupled with sequencing (ChIP-Seq). Elucidation of the miRNA target repertoire will provide an in-depth understanding of the functional roles of microRNA pathways. To reliably reconstruct a miRNA-mediated regulatory network, we established a computational framework using publicly available, sequence-based transcription factor-miRNA databases, including ChIPBase and TransmiR for the TF-miRNA interactions, along with miRNA-target databases, including miRTarBase, TarBase and starBase, for the miRNA-target interactions. We applied the computational framework to elucidate the miRNA-mediated regulatory network in the Mir122a(-/-) mouse model, which has an altered transcriptome and progressive liver disease. Results: We applied our computational framework to the expression profiles of miRNA/mRNA of Mir122a(-/-) mutant mice and wild-type mice. The miRNA-mediated network involves 40 curated TFs contributing to the aberrant expression of 65 miRNAs and 723 curated miRNA target genes, of which 56% was found in the differentially-expressed genes of Mir122a(-) mice. Hence, the regulatory network disclosed previously-known and also many previously-unidentified miRNA-mediated regulations in mutant mice. Moreover, we demonstrate that loss of imprinting at the chromosome 12qF1 region is associated with miRNA overexpression in human hepatocellular carcinoma and stem cells, suggesting initiation of precancerous changes in young mice deficient in miR-122. A group of 9 miRNAs was found to share miR-122 target genes, indicating synergy between miRNAs and target genes by way of multiplicity and cooperativity. Conclusions: The study provides significant insight into miRNA-mediated regulatory networks. Based on experimentally verified data, this network is highly reliable and effective in revealing previously-undetermined disease-associated molecular mechanisms. This computational framework can be applied to explore the significant TF-miRNA-miRNA target interactions in any complex biological systems with high degrees of confidence.en_US
dc.language.isoen_USen_US
dc.titleIntegrated analyses to reconstruct microRNA-mediated regulatory networks in mouse liver using high-throughput profilingen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/1471-2164-16-S2-S12en_US
dc.identifier.journalBMC GENOMICSen_US
dc.citation.volume16en_US
dc.citation.spage0en_US
dc.citation.epage0en_US
dc.contributor.department生物科技學系zh_TW
dc.contributor.department生物資訊及系統生物研究所zh_TW
dc.contributor.department生物資訊研究中心zh_TW
dc.contributor.departmentDepartment of Biological Science and Technologyen_US
dc.contributor.departmentInstitude of Bioinformatics and Systems Biologyen_US
dc.contributor.departmentCenter for Bioinformatics Researchen_US
dc.identifier.wosnumberWOS:000353978900012en_US
dc.citation.woscount6en_US
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