RNA Polymerase II Binding Patterns Reveal Genomic Regions Involved in MicroRNA Gene Regulation

University of Calgary, Canada
PLoS ONE (Impact Factor: 3.23). 11/2010; 5(11):e13798. DOI: 10.1371/journal.pone.0013798
Source: PubMed


MicroRNAs are small non-coding RNAs involved in post-transcriptional regulation of gene expression. Due to the poor annotation of primary microRNA (pri-microRNA) transcripts, the precise location of promoter regions driving expression of many microRNA genes is enigmatic. This deficiency hinders our understanding of microRNA-mediated regulatory networks. In this study, we develop a computational approach to identify the promoter region and transcription start site (TSS) of pri-microRNAs actively transcribed using genome-wide RNA Polymerase II (RPol II) binding patterns derived from ChIP-seq data. Based upon the assumption that the distribution of RPol II binding patterns around the TSS of microRNA and protein coding genes are similar, we designed a statistical model to mimic RPol II binding patterns around the TSS of highly expressed, well-annotated promoter regions of protein coding genes. We used this model to systematically scan the regions upstream of all intergenic microRNAs for RPol II binding patterns similar to those of TSS from protein coding genes. We validated our findings by examining the conservation, CpG content, and activating histone marks in the identified promoter regions. We applied our model to assess changes in microRNA transcription in steroid hormone-treated breast cancer cells. The results demonstrate many microRNA genes have lost hormone-dependent regulation in tamoxifen-resistant breast cancer cells. MicroRNA promoter identification based upon RPol II binding patterns provides important temporal and spatial measurements regarding the initiation of transcription, and therefore allows comparison of transcription activities between different conditions, such as normal and disease states.

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    • "However, RNA polymerase II transcribes miRNA like mRNA and the same transcription factors are involved in miRNA transcription as that of mRNA transcription (Wang et al., 2010a,b). The chromosomes having high number of miRNA genes are more crucial for several cellular processes including different diseases . "
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    Frontiers in Genetics 04/2014; 5:100. DOI:10.3389/fgene.2014.00100
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    • "This led to the identification of another 274 MIR TSSs. We also predicted the promoter regions and TSSs of MIRs using genome-wide RNAPII binding peaks derived from ChIA-PET data (22), which is based on the previous observation that RNAPII binding peaks are proximal to the TSS of MIRs (38). The nearest RNAPII peak within 50 kb upstream of pre-miRNA was assigned to the TSS of that MIR. "
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    ABSTRACT: Our knowledge of the role of higher-order chromatin structures in transcription of microRNA genes (MIRs) is evolving rapidly. Here we investigate the effect of 3D architecture of chromatin on the transcriptional regulation of MIRs. We demonstrate that MIRs have transcriptional features that are similar to protein-coding genes. RNA polymerase II–associated ChIA-PET data reveal that many groups of MIRs and protein-coding genes are organized into functionally compartmentalized chromatin communities and undergo coordinated expression when their genomic loci are spatially colocated. We observe that MIRs display widespread communication in those transcriptionally active communities. Moreover, miRNA–target interactions are significantly enriched among communities with functional homogeneity while depleted from the same community from which they originated, suggesting MIRs coordinating function-related pathways at posttranscriptional level. Further investigation demonstrates the existence of spatial MIR–MIR chromatin interacting networks. We show that groups of spatially coordinated MIRs are frequently from the same family and involved in the same disease category. The spatial interaction network possesses both common and cell-specific subnetwork modules that result from the spatial organization of chromatin within different cell types. Together, our study unveils an entirely unexplored layer of MIR regulation throughout the human genome that links the spatial coordination of MIRs to their co-expression and function.
    Nucleic Acids Research 12/2013; 42(5). DOI:10.1093/nar/gkt1294 · 9.11 Impact Factor
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    • "This has been recently employed to identify miRNA promoters regulated by ERα, ERβ and TCF4 in cancer cell lines [86-88]. In addition, genome-wide binding patterns of RNA Polymerase II have been used to identify promoters of miRNAs actively transcribed [89]. Applications of these approaches in clinical samples will provide new insights into the dynamic functions of various transcription factors in miRNA deregulation in different types and subtypes of cancer and at different stages of cancer progression. "
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    ABSTRACT: The discovery of microRNAs (miRNAs) has opened up new avenues for studying cancer at the molecular level, featuring a post-genomic era of biomedical research. These non-coding regulatory RNA molecules of ~22 nucleotides have emerged as important cancer biomarkers, effectors, and targets. In this review, we focus on the dysregulated biogenesis and function of miRNAs in cancers with an overexpression of the proto-oncogene HER2. Many of the studies reviewed here were carried out in breast cancer, where HER2 overexpression has been extensively studied and HER2-targeted therapy practiced for more than a decade. MiRNA signatures that can be used to classify tumors with different HER2 status have been reported but little consensus can be established among various studies, emphasizing the needs for additional well-controlled profiling approaches and meta-analyses in large and well-balanced patient cohorts. We further discuss three aspects of microRNA dysregulation in or contribution to HER2-associated malignancies or therapies: (a) miRNAs that are up- or down-regulated by HER2 and mediate the downstream signaling of HER2; (b) miRNAs that suppress the expression of HER2 or a factor in HER2 receptor complexes, such as HER3; and (c) miRNAs that affect responses to anti-HER2 therapies. The regulatory mechanisms are elaborated using mainly examples of miR- 205, miR-125, and miR-21. Understanding the regulation and function of miRNAs in HER2-overexpressing tumors shall shed new light on the pathogenic mechanisms of microRNAs and the HER2 proto-oncogene in cancer, as well as on individualized or combinatorial anti-HER2 therapies.
    09/2013; 2(2):137-47. DOI:10.2174/22115366113029990011
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