Browsing by Subject "mirna"

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miR-503 Represses Human Cell Proliferation and Directly Targets the Oncogene DDHD2 by Non-Canonical Target Pairing
(2015-02) Polioudakis, Damon; Abell, Nathan S.; Iyer, Vishwanath R.; Polioudakis, Damon; Abell, Nathan S.; Iyer, Vishwanath R.
The pathways regulating the transition of mammalian cells from quiescence to proliferation are mediated by multiple miRNAs. Despite significant improvements in our understanding of miRNA targeting, the majority of miRNA regulatory networks are still largely unknown and require experimental validation. Results: Here we identified miR-503, miR-103, and miR-494 as negative regulators of proliferation in primary human cells. We experimentally determined their genome wide target profiles using RNA-induced silencing complex (RISC) immunoprecipitations and gene expression profiling. Analysis of the genome wide target profiles revealed evidence of extensive regulation of gene expression through non-canonical target pairing by miR-503. We identified the proto-oncogene DDHD2 as a target of miR-503 that requires pairing outside of the canonical 5' seed region of miR-503, representing a novel mode of miRNA-target pairing. Further bioinformatics analysis implicated miR-503 and DDHD2 in breast cancer tumorigenesis. Conclusions: Our results provide an extensive genome wide set of targets for miR-503, miR-103, and miR-494, and suggest that miR-503 may act as a tumor suppressor in breast cancer by its direct non-canonical targeting of DDHD2.
Positively Correlated miRNA-miRNA Regulatory Networks in Mouse Frontal Cortex During Early Stages of Alcohol Dependence
(2013-10) Nunez, Yury O.; Truitt, Jay M.; Gorini, Giorgio; Ponomareva, Olga N.; Blednov, Yuri A.; Harris, R. Adon; Mayfield, R. Dayne; Positively Correlated miRNA-miRNA Regulatory Networks in Mouse Frontal Cortex During Early Stages of Alcohol Dependence
Although the study of gene regulation via the action of specific microRNAs (miRNAs) has experienced a boom in recent years, the analysis of genome-wide interaction networks among miRNAs and respective targeted mRNAs has lagged behind. MicroRNAs simultaneously target many transcripts and fine-tune the expression of genes through cooperative/combinatorial targeting. Therefore, they have a large regulatory potential that could widely impact development and progression of diseases, as well as contribute unpredicted collateral effects due to their natural, pathophysiological, or treatment-induced modulation. We support the viewpoint that whole mirnome-transcriptome interaction analysis is required to better understand the mechanisms and potential consequences of miRNA regulation and/or deregulation in relevant biological models. In this study, we tested the hypotheses that ethanol consumption induces changes in miRNA-mRNA interaction networks in the mouse frontal cortex and that some of the changes observed in the mouse are equivalent to changes in similar brain regions from human alcoholics. Results: miRNA-mRNA interaction networks responding to ethanol insult were identified by differential expression analysis and weighted gene coexpression network analysis (WGCNA). Important pathways (coexpressed modular networks detected by WGCNA) and hub genes central to the neuronal response to ethanol are highlighted, as well as key miRNAs that regulate these processes and therefore represent potential therapeutic targets for treating alcohol addiction. Importantly, we discovered a conserved signature of changing miRNAs between ethanol-treated mice and human alcoholics, which provides a valuable tool for future biomarker/diagnostic studies in humans. We report positively correlated miRNA-mRNA expression networks that suggest an adaptive, targeted miRNA response due to binge ethanol drinking. Conclusions: This study provides new evidence for the role of miRNA regulation in brain homeostasis and sheds new light on current understanding of the development of alcohol dependence. To our knowledge this is the first report that activated expression of miRNAs correlates with activated expression of mRNAs rather than with mRNA downregulation in an in vivo model. We speculate that early activation of miRNAs designed to limit the effects of alcohol-induced genes may be an essential adaptive response during disease progression.
Unique Patterns of Transcript and miRNA Expression in the South American Strong Voltage Electric Eel (Electrophorus Electricus)
(2015-03) Traeger, Lindsay L.; Volkening, Jeremy D.; Moffett, Howell; Gallant, Jason R.; Chen, Po-Hao; Novina, Carl D.; Phillips, George N., Jr.; Anand, Rene; Wells, Gregg B.; Pinch, Matthew; Gueth, Robert; Unguez, Graciela A.; Albert, James S.; Zakon, Harold; Sussman, Michael R.; Samanta, Manoj P.; Zakon, Harold
With its unique ability to produce high-voltage electric discharges in excess of 600 volts, the South American strong voltage electric eel (Electrophorus electricus) has played an important role in the history of science. Remarkably little is understood about the molecular nature of its electric organs. Results: We present an in-depth analysis of the genome of E. electricus, including the transcriptomes of eight mature tissues: brain, spinal cord, kidney, heart, skeletal muscle, Sachs' electric organ, main electric organ, and Hunter's electric organ. A gene set enrichment analysis based on gene ontology reveals enriched functions in all three electric organs related to transmembrane transport, androgen binding, and signaling. This study also represents the first analysis of miRNA in electric fish. It identified a number of miRNAs displaying electric organ-specific expression patterns, including one novel miRNA highly over-expressed in all three electric organs of E. electricus. All three electric organ tissues also express three conserved miRNAs that have been reported to inhibit muscle development in mammals, suggesting that miRNA-dependent regulation of gene expression might play an important role in specifying an electric organ identity from its muscle precursor. These miRNA data were supported using another complete miRNA profile from muscle and electric organ tissues of a second gymnotiform species. Conclusions: Our work on the E. electricus genome and eight tissue-specific gene expression profiles will greatly facilitate future research on determining the coding and regulatory sequences that specify the function, development, and evolution of electric organs. Moreover, these data and future studies will be informed by the first comprehensive analysis of miRNA expression in an electric fish presented here.