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      Large scale chromosomal mapping of human microRNA structural clusters

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      Author(s): , *
      Publication date (Electronic):
      Journal: Nucleic Acids Research
      Publisher: Oxford University Press

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          Abstract

          MicroRNAs (miRNAs) can group together along the human genome to form stable secondary structures made of several hairpins hosting miRNAs in their stems. The few known examples of such structures are all involved in cancer development. A large scale computational analysis of human chromosomes crossing sequence analysis and deep sequencing data revealed the presence of >400 structural clusters of miRNAs in the human genome. An a posteriori analysis validates predictions as bona fide miRNAs. A functional analysis of structural clusters position along the chromosomes co-localizes them with genes involved in several key cellular processes like immune systems, sensory systems, signal transduction and development. Immune systems diseases, infectious diseases and neurodegenerative diseases are characterized by genes that are especially well organized around structural clusters of miRNAs. Target genes functional analysis strongly supports a regulatory role of most predicted miRNAs and, notably, a strong involvement of predicted miRNAs in the regulation of cancer pathways. This analysis provides new fundamental insights on the genomic organization of miRNAs in human chromosomes.

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          Prediction of mammalian microRNA targets.

          Benjamin Lewis, I-hung Shih, Matthew W Jones-Rhoades … (2003)
          MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
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            Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

            Andrea Bild, Guang Yao, Jeffrey Chang … (2006)
            The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.
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              Identification of mammalian microRNA host genes and transcription units.

              Antony Rodriguez, Sam Griffiths-Jones, Jennifer Ashurst … (2004)
              To derive a global perspective on the transcription of microRNAs (miRNAs) in mammals, we annotated the genomic position and context of this class of noncoding RNAs (ncRNAs) in the human and mouse genomes. Of the 232 known mammalian miRNAs, we found that 161 overlap with 123 defined transcription units (TUs). We identified miRNAs within introns of 90 protein-coding genes with a broad spectrum of molecular functions, and in both introns and exons of 66 mRNA-like noncoding RNAs (mlncRNAs). In addition, novel families of miRNAs based on host gene identity were identified. The transcription patterns of all miRNA host genes were curated from a variety of sources illustrating spatial, temporal, and physiological regulation of miRNA expression. These findings strongly suggest that miRNAs are transcribed in parallel with their host transcripts, and that the two different transcription classes of miRNAs ('exonic' and 'intronic') identified here may require slightly different mechanisms of biogenesis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nucleic Acids Res
                Journal ID (iso-abbrev): Nucleic Acids Res
                Journal ID (publisher-id): nar
                Journal ID (hwp): nar
                Title: Nucleic Acids Research
                Publisher: Oxford University Press
                ISSN (Print): 0305-1048
                ISSN (Electronic): 1362-4962
                Publication date (Print): April 2013
                Publication date (Electronic): 26 February 2013
                Publication date PMC-release: 26 February 2013
                Volume: 41
                Issue: 8
                Pages: 4392-4408
                Affiliations
                1Université Pierre et Marie Curie, UMR7238, 15, rue de l’Ecole de Médecine, 75006 Paris, France and 2CNRS, UMR7238, Laboratoire de Génomique des Microorganismes, 75006 Paris, France
                Author notes
                *To whom correspondence should be addressed. Tel: +33 1 44 27 73 45; Fax: +33 1 44 27 73 36; Email: Alessandra.Carbone@ 123456lip6.fr
                Article
                Publisher ID: gkt112
                DOI: 10.1093/nar/gkt112
                PMC ID: 3632110
                PubMed ID: 23444140
                SO-VID: 2ec4e5c3-41ce-4109-b46e-2519c5860203
                Copyright © © The Author(s) 2013. Published by Oxford University Press.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 19 October 2012
                Date revision received : 8 January 2013
                Date accepted : 3 February 2013
                Page count
                Pages: 17
                Categories
                Subject: Computational Biology

                ScienceOpen disciplines: Genetics
                Data availability:
                ScienceOpen disciplines: Genetics

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