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      microRNA Expression Patterns Reveal Differential Expression of Target Genes with Age

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          Abstract

          Recent evidence supports a role for microRNAs (miRNAs) in regulating the life span of model organisms. However, little is known about how these small RNAs contribute to human aging. Here, we profiled the expression of over 800 miRNAs in peripheral blood mononuclear cells from young and old individuals by real-time RT-PCR analysis. This genome-wide assessment of miRNA expression revealed that the majority of miRNAs studied decreased in abundance with age. We identified nine miRNAs (miR-103, miR-107, miR-128, miR-130a, miR-155, miR-24, miR-221, miR-496, miR-1538) that were significantly lower in older individuals. Among them, five have been implicated in cancer pathogenesis. Predicted targets of several of these miRNAs, including PI3 kinase (PI3K), c-Kit and H2AX, were found to be elevated with advancing age, supporting a possible role for them in the aging process. Furthermore, we found that decreasing the levels of miR-221 was sufficient to cause a corresponding increase in the expression of the predicted target, PI3K. Taken together, these findings demonstrate that changes in miRNA expression occur with human aging and suggest that miRNAs and their predicted targets have the potential to be diagnostic indicators of age or age-related diseases.

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          Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection.

          Jason Wong, Linda C. Li (2001)
          Recent advances in cDNA and oligonucleotide DNA arrays have made it possible to measure the abundance of mRNA transcripts for many genes simultaneously. The analysis of such experiments is nontrivial because of large data size and many levels of variation introduced at different stages of the experiments. The analysis is further complicated by the large differences that may exist among different probes used to interrogate the same gene. However, an attractive feature of high-density oligonucleotide arrays such as those produced by photolithography and inkjet technology is the standardization of chip manufacturing and hybridization process. As a result, probe-specific biases, although significant, are highly reproducible and predictable, and their adverse effect can be reduced by proper modeling and analysis methods. Here, we propose a statistical model for the probe-level data, and develop model-based estimates for gene expression indexes. We also present model-based methods for identifying and handling cross-hybridizing probes and contaminating array regions. Applications of these results will be presented elsewhere.
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            Impaired microRNA processing enhances cellular transformation and tumorigenesis.

            Madhu S. Kumar, Jun Lu, Kim Mercer … (2007)
            MicroRNAs (miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in proliferation, differentiation and apoptosis, processes commonly altered during tumorigenesis. Recent work has shown a global decrease of mature miRNA expression in human cancers. However, it is unclear whether this global repression of miRNAs reflects the undifferentiated state of tumors or causally contributes to the transformed phenotype. Here we show that global repression of miRNA maturation promotes cellular transformation and tumorigenesis. Cancer cells expressing short hairpin RNAs (shRNAs) targeting three different components of the miRNA processing machinery showed a substantial decrease in steady-state miRNA levels and a more pronounced transformed phenotype. In animals, miRNA processing-impaired cells formed tumors with accelerated kinetics. These tumors were more invasive than control tumors, suggesting that global miRNA loss enhances tumorigenesis. Furthermore, conditional deletion of Dicer1 enhanced tumor development in a K-Ras-induced mouse model of lung cancer. Overall, these studies indicate that abrogation of global miRNA processing promotes tumorigenesis.
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              Widespread microRNA repression by Myc contributes to tumorigenesis.

              Tsung-Cheng Chang, Duonan Yu, Yun-Sil Lee … (2008)
              The c-Myc oncogenic transcription factor (Myc) is pathologically activated in many human malignancies. Myc is known to directly upregulate a pro-tumorigenic group of microRNAs (miRNAs) known as the miR-17-92 cluster. Through the analysis of human and mouse models of B cell lymphoma, we show here that Myc regulates a much broader set of miRNAs than previously anticipated. Unexpectedly, the predominant consequence of activation of Myc is widespread repression of miRNA expression. Chromatin immunoprecipitation reveals that much of this repression is likely to be a direct result of Myc binding to miRNA promoters. We further show that enforced expression of repressed miRNAs diminishes the tumorigenic potential of lymphoma cells. These results demonstrate that extensive reprogramming of the miRNA transcriptome by Myc contributes to tumorigenesis.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2010
                Publication date (Electronic): 20 May 2010
                Volume: 5
                Issue: 5
                Electronic Location Identifier: e10724
                Affiliations
                [1 ]Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
                [2 ]Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
                [3 ]Laboratory of Personality and Cognition, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
                Roswell Park Cancer Institute, United States of America
                Author notes

                Conceived and designed the experiments: NNH KA MG MKE. Performed the experiments: NNH KA. Analyzed the data: NNH MKE. Contributed reagents/materials/analysis tools: NE ABZ. Wrote the paper: NNH. Examined and evaluated human participants: NE. Co-principal investigator on clinical observational study: ABZ.

                Article
                Publisher ID: 10-PONE-RA-15575R1
                DOI: 10.1371/journal.pone.0010724
                PMC ID: 2873959
                PubMed ID: 20505758
                SO-VID: f0dff2e1-363e-4096-a2ac-a0c9bd1be0d2
                Copyright © This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                History
                Date received : 15 January 2010
                Date accepted : 27 April 2010
                Page count
                Pages: 13
                Categories
                Subject: Research Article
                Subject: Molecular Biology
                Subject: Cell Biology/Gene Expression
                Subject: Developmental Biology/Aging

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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