title: The regulatory epicenter of miRNAs.
abstract: 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 upstreamregions, 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 overrepresented 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, coexpression 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 inmiRNA 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.
authors.affiliation: Studio of Computational Biology and Bioinformatics, Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Council of Scientific and Industrial Research, Palampur 176061, HP, India.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Jha
authors.forename: Mrigaya
authors.initials: M
authors.lastname: Mehra
authors.forename: Ravi
authors.initials: R
authors.lastname: Shankar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C408087:DICER1 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases