The regulatory epicenter of miRNAs
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miRNAs are small non-coding RNAs with average length of ~21 bp. miRNA formation seems to be dependent upon multiple factors besides Drosha and Dicer, in a tissue/stage-specific manner, with interplay of several specific binding factors. In the present study, we have investigated transcription factor binding sites in and around the genomic sequences of precursor miRNAs and RNA-binding protein (RBP) sites in miRNA precursor sequences, analysed and tested in comprehensive manner. Here, we report that miRNA precursor regions are positionally enriched for binding of transcription factors as well as RBPs around the 3′ end of mature miRNA region in 5′ arm. The pattern and distribution of such regulatory sites appears to be a characteristic of precursor miRNA sequences when compared with non-miRNA sequences as negative dataset and tested statistically. When compared with 1 kb upstream regions, a sudden sharp peak for binding sites arises in the enriched zone near the mature miRNA region. An expression-data-based correlation analysis was performed between such miRNAs and their corresponding transcription factors and RBPs for this region. Some specific groups of binding factors and associated miRNAs were identified. We also identified some of the over-represented transcription factors and associated miRNAs with high expression correlation values which could be useful in cancer-related studies. The highly correlated groups were found to host experimentally validated composite regulatory modules, in which Lmo2-GATA1 appeared as the predominant one. For many of RBP–miRNAs associations, co-expression similarity was also evident among the associated miRNA common to given RBPs, supporting the Regulon model, suggesting a common role and common control of these miRNAs by the associated RBPs. Based on our findings, we propose that the observed characteristic distribution of regulatory sites in precursor miRNA sequence regions could be critical in miRNA transcription, processing, stability and formation and are important for therapeutic studies. Our findings also support the recently proposed theory of self-sufficient mode of transcription by miRNAs, which states that miRNA transcription can be carried out in host-independent mode too.
KeywordsBiogenesis miRNA precursor RBP TFBS transcription
We are thankful to Department of Biotechnology for the fellowship to AJ. MM is thankful to Council of Scientific and Industrial Research, India, for her JRF fellowship. We thank Amit Chaurasia and Dr Mitali Mukerji, IGIB, for sharing TFBS data for human.
The present research work was funded by DBT, India, grant number: BT/PR-11098/BID/07/261/2008 and CSIR grant OLP-0037. We are thankful to Dr PS Ahuja, IHBT, for helping us with internal funding MLP0037. The IHBT communication ID for this manuscript is: 3165.
- Abeel A, Peer YV and Saeys Y 2009 Toward a gold standard for promoter prediction evaluation. Bioinformatics 25 i313–i320Google Scholar
- Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, et al. 2007 Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol. Cell 26 745–752Google Scholar
- Dinger ME, Amaral PP, Mercer TR and Mattick JS 2009 Pervasive transcription of the exukaryotic genome: functional indices and conceptual implications. Brief. Bioinformatics 8 407–423Google Scholar
- Guil S and Cáceres JF 2007 The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat. Struct. Mol. Biol. 14 591–596Google Scholar
- Isik M, Korswagen HC and Berezikov E 2010 Expression patterns of intronic microRNAs in Caenorhabditis elegans. Silence 1 5Google Scholar
- Kanhoush R, Beenders B, Perrin C, Moreau J, Bellini M and Penrad-Mobayed M 2009 Novel domains in the hnRNP G/RBMX protein with distinct roles in RNA binding and targeting nascent transcripts. Nucleus 1 109–122Google Scholar
- Kedde M, van Kouwenhove M, Zwart W, Oude Vrielink JA, Elkon R and Agami R 2010 A Pumilio-induced RNA structure switch in p27-3′ UTR controls miR-221 and miR-222 accessibility. Nat. Cell Biol. 12 1014–1020Google Scholar
- Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, Meister G and Hermeking H 2007 Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 6 1586–1593Google Scholar
- Wu H, Sun S, Tu K, Gao Y, Xie B, Krainer AR and Zhu J 2010 A splicing-independent function of SF2/ASF in microRNA processing. Mol. Cell 38 67–77Google Scholar