Polymorphic Polymorphic MicroRNA-Target Interactions: A Novel Source of Phenotypic Variation

Georges, Michel; Clop, Alex; Marcq, Fabienne; Takeda, Hitoshi; Pirottin, Dimitri; Hiard, Samuel; Tordoir, Xavier; Caiment, Florian; Meish, Françoise; Bibé, Bernard; Bouix, Jacques; Elsen, Jean-Michel; Eychenne, Francis; Laville, Élisabeth; Larzul, Catherine; Milenković, Dragan; Tobin, James F.; Charlier, Carole

doi:10.1101/sqb.2006.71.056

Cited by 47 publications

(39 citation statements)

References 20 publications

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“…Patrocles (Georges et al, 2006) to determine whether any of these 3Ј-UTR SNPs that exists in miRNA target sites are predicted to affect the base-pairing between HNF4A mRNA and the target miRNAs. There were five SNPs in the HNF4A gene that are predicted to destroy six miRNA target sites and create two new miRNA target sites (Supplemental Table 3).…”

Section: Resultsmentioning

confidence: 99%

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In Silico and In Vitro Identification of MicroRNAs That Regulate Hepatic Nuclear Factor 4α Expression

Ramamoorthy¹,

Li²,

Gaedigk³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Hepatic nuclear factor 4␣ (HNF4A) is a nuclear transcription factor that regulates the expression of many genes involved in drug disposition. To identify additional molecular mechanisms that regulate HNF4A, we identified microRNAs (miRNAs) that target HNF4A expression. In silico analyses suggested that HNF4A is targeted by many miRNAs. We conducted in vitro studies to validate several of these predictions. With use of an HNF4A 3-untranslated region (UTR) luciferase reporter assay, five of six miRNAs tested significantly downregulated (ϳ20-40%) the luciferase activity. In HepG2 cells, miR-34a and miR-449a also down-regulated the expression of both the HNF4A protein and an HNF4A target gene, PXR (ϳ30-40%). This regulation appeared without reduction in HNF4A mRNA expression, suggesting that they must be blocking HNF4A translation. Using additional bioinformatic algorithms, we identified polymorphisms that are predicted to alter the miRNA targeting of HNF4A. Luciferase assays indicated that miR-34a and miR-449a were less effective in regulating a variant (rs11574744) than the wild-type HNF4A 3-UTR. In vivo, subjects with the variant HNF4A had lower CYP2D6 enzyme activity, although this result was not statistically significant (p ‫؍‬ 0.16). In conclusion, our findings demonstrate strong evidence for a role of miRNAs in the regulation of HNF4A.

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Section: Resultsmentioning

confidence: 99%

“…The minor allele frequencies were obtained from dbSNP and SeattleSNPs database (http://pga.gs.washington.edu). We used two programs, PolymiRTS Database (Bao et al, 2007) and Patrocles (Georges et al, 2006) to predict the effect of miRSNPs in the HNF4A 3Ј-UTR on the mRNA-miRNA interaction.…”

Section: Methodsmentioning

confidence: 99%

In Silico and In Vitro Identification of MicroRNAs That Regulate Hepatic Nuclear Factor 4α Expression

Ramamoorthy¹,

Li²,

Gaedigk³

et al. 2012

Drug Metab Dispos

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show abstract

“…Unfortunately, as intriguing as these SNPs may be, there currently is insufficient population allele frequency data to assess their functional significance. In addition to PolymiRTS, a second, searchable miRNA SNP database called Patrocles is available (http://www.patrocles.org/Patrocles_targets.htm) [99]. A list of human and mouse genes with SNPs that alter miR-206 binding sites, as identified by PolymiRTS and Patrocles databases, is provided as supplemental data (Table S7 and Table S8).…”

Section: Polymorphismsmentioning

confidence: 99%

MicroRNA-206: The skeletal muscle-specific myomiR

McCarthy

2008

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

367

317

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MicroRNAs (miRNAs) are a class of non-coding RNAs involved in post-transcriptional gene silencing. A small number of striated muscle-specific miRNAs have been identified and shown to have an important role in myogenesis, embryonic muscle growth and cardiac function and hypertrophy. One of these myomiRs (myo = muscle + miR = miRNA), miR-206, is unique in that it is only expressed in skeletal muscle. The purpose of this review is to discuss what is currently known about miR-206 and its function in myogenesis as well as propose potential new roles for miR-206 in skeletal muscle biology. The review is also intended to serve as a comprehensive resource for miR-206 with the hope of encouraging further research on the role of miR-206 in skeletal muscle.

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“…Furthermore, the significant numbers of single nucleotide polymorphisms in the human genome could potentially create or disrupt the putative miRNA target sites. Therefore, variations in the target mRNA sequences could also modulate the activity of specific miRNAs and contribute to phenotypic variation [43,44]. It is likely that many of these variations would affect neuronal miRNAs.…”

Section: Down Syndromementioning

confidence: 97%

Small RNA-Mediated Gene Regulation in Neurodevelopmental Disorders

Qurashi

Jin

2010

Curr Psychiatry Rep

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An expanding assortment of small, noncoding RNAs identified in the nervous system suggests a strong connection between their combinatorial regulatory potential and the complexity of the nervous system. Misregulation of these small regulatory RNAs could contribute to the abnormalities in brain development that are associated with neurodevelopmental disorders. Here we give an overview of the diversity and unexpected abundance of small RNAs, as well as specific examples that illustrate their functional significance in neurodevelopmental disorders. We also discuss an intriguing, albeit elusive area of study: the potential impact of newly discovered classes of small RNAs in the nervous system.

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Polymorphic Polymorphic MicroRNA-Target Interactions: A Novel Source of Phenotypic Variation

Cited by 47 publications

References 20 publications

In Silico and In Vitro Identification of MicroRNAs That Regulate Hepatic Nuclear Factor 4α Expression

In Silico and In Vitro Identification of MicroRNAs That Regulate Hepatic Nuclear Factor 4α Expression

MicroRNA-206: The skeletal muscle-specific myomiR

Small RNA-Mediated Gene Regulation in Neurodevelopmental Disorders

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