Genome-Wide Identification of Estrogen Receptor Alpha Regulated miRNAs Using Transcription Factor Binding Data

MicroRNAs (miRNAs) are one class of endogenous non-coding RNA which can repress protein translation or cause target mRNA degradation(Bartel 2004). Currently 15,172 entries, including 1,048 human miRNAs, are recorded in a major miRNAs database miRbase (Release 16: Sept 2010) (Kozomara and Griffiths-Jones 2011). MiRNAs reside reside in protein-coding, intronic and intergenic regions throughout the genome. MiRNAs are mainly transcribed into long primary miRNAs (pri-miRNAs) by RNA polymerase II(Lee et al. 2004). Since mammalian miRNA genes are often clustered along the genome, the pri-miRNA can contain one single miRNA gene or multiple clustered miRNA genes. In the nucleus, primiRNAs, which are both capped and polyadenylated, are processed by RNase III enzymes Drosha into about 70-nucleotide hairpins called pre-miRNAs(Lee et al. 2002). The transporter protein exportin-5 then exports pre-miRNAs to the cytoplasm, where they are cleaved by another RNase III Dicer to generate mature miRNA duplexes. One strand of miRNA duplex preferentially enters into miRNA-induced silencing complexes (miRISCs) and guides the complex to recognize its target genes. Previous studies indicated that this target inhibition of miRNAs mainly function via imperfect base pairing with the targeting sequences on the 3’ untranslated region(3'UTR) and the first 2–8 bases of a particular mature miRNA sequence referred to the ”seed’’ region. MiRNAs play essential regulatory roles in diverse biological processes. For example, we recently found that miRNA-153, the expression level of which is significantly repressed in glioblastoma (GBM), could inhibit cell proliferation and induce apoptosis via targeting B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia sequence 1 (Mcl-1) and insulin receptor substrate-2 (Irs-2) in glioblastoma cell lines(Xu, Liao, and Wong 2010; Xu et al. 2011). In the past few years, computational approaches have played an important role in miRNA studies, for example, dozens of prediction tools used for miRNA gene finding and miRNA target prediction were developed. These tools have greatly facilitated experimental discovery. However, knowledge about the regulation of these essential regulators is at its early stage(Schanen and Li 2010; Li et al. 2010). Transcriptional regulations mediated by specific transcriptional factors (TFs) have only been intensively studied on a small number of miRNAs(Lee et al. 2004; Houbaviy et al. 2005). Importantly, certain “oncogenic miRNAs”