Inferring causative variants in microRNA target sites

Thomas, Laurent F.; Saito, Takaya; Sætrom, Pål

doi:10.1093/nar/gkr414

Cited by 65 publications

(53 citation statements)

References 37 publications

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“…The miRNA-SNP online prediction tool, mirsnpscore available at www.bigr.medisin.ntnu.no/mirsnpscore (Thomas et al 2011), was used to identify miR-191-5p, miR-887 and miR-3669 (Eeles et al 2013) all predicted to preferentially target the MDM4 rs4245739 SNP C-allele. To validate in silico predictions for miRNA-SNP affinity, miRNA target luciferase reporter vector assays were performed.…”

Section: Mirna Target Reporter Vector Assaysmentioning

confidence: 99%

“…miR-191-5p and miR-887 have a higher affinity for the MDM4 rs4245739 SNP C-allele Using mirsnpscore (www.bigr.medisin.ntnu.no/mirsnpscore; (Thomas et al 2011)), MDM4 rs4245739 SNP was predicted to affect the binding of three miRNAs to the MDM4 3 0 -UTR (Eeles et al 2013). These included miR-191-5p, miR-887 and miR-3669, which were all predicted to have a higher affinity for the C-allele ( Fig.…”

Section: Mdm4 Expression Is Associated With Metastasis and Recurrencementioning

confidence: 99%

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A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer

Stegeman¹,

Moya²,

Selth³

et al. 2015

Endocrine-Related Cancer

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The oncogene MDM4, also known as MDMX or HDMX, contributes to cancer susceptibility and progression through its capacity to negatively regulate a range of genes with tumoursuppressive functions. As part of a recent genome-wide association study it was determined that the A-allele of the rs4245739 SNP (AOC), located in the 3 0 -UTR of MDM4, is associated with an increased risk of prostate cancer. Computational predictions revealed that the rs4245739 SNP is located within a predicted binding site for three microRNAs (miRNAs): miR-191-5p, miR-887 and miR-3669. Herein, we show using reporter gene assays and endogenous MDM4 expression analyses that miR-191-5p and miR-887 have a specific affinity for the rs4245739 SNP C-allele in prostate cancer. These miRNAs do not affect MDM4 mRNA levels, rather they inhibit its translation in C-allele-containing PC3 cells but not in LNCaP cells homozygous for the A-allele. By analysing gene expression datasets from patient cohorts, we found that MDM4 is associated with metastasis and prostate cancer progression and that targeting this gene with miR-191-5p or miR-887 decreases in PC3 cell viability. This study is the first, to our knowledge, to demonstrate regulation of the MDM4 rs4245739 SNP C-allele by two miRNAs in prostate cancer, and thereby to identify a mechanism by which the MDM4 rs4245739 SNP A-allele may be associated with an increased risk for prostate cancer.Key Words " MDM4" microRNA " single nucleotide polymorphism " prostate cancer

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Section: Mirna Target Reporter Vector Assaysmentioning

confidence: 99%

Section: Mdm4 Expression Is Associated With Metastasis and Recurrencementioning

confidence: 99%

A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer

Stegeman¹,

Moya²,

Selth³

et al. 2015

Endocrine-Related Cancer

View full text Add to dashboard Cite

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“…Genetic variations in the regulatory regions of genes can potentially result in altered protein levels 53. Polymorphisms within microRNA binding sites in the 3′ untranslated region of candidate genes for colorectal cancer have been linked to colorectal cancer formation 54.…”

Section: Correlating Gene Expression With Linkage and Genome-wide Assmentioning

confidence: 99%

Whole genome and global expression profiling of Dupuytren's disease: systematic review of current findings and future perspectives

2012

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Dupuytren's disease (DD) is a common fibroproliferative disorder affecting the palmar fascia, which may lead to permanent contracture of the affected digit. Profiling studies investigating DD at whole-genomic, transcriptomic and proteomic levels have been carried out, from which large numbers of candidate genes potentially involved in DD have been reported. This review focuses on identifying genes reported by multiple studies or validated by multiple experimental techniques, as well as signalling pathways suggested to contribute to DD. Meta-analysis was also carried out on three microarray datasets. Twenty-one genes were found to be reported as dysregulated in multiple gene expression microarrays, seven of which have been further validated by other experimental methods. Sixty-four genes determined to be dsyregulated by meta-analysis correlate to those reported by published microarray studies. In addition, several pathways have been proposed to be involved in DD by whole-genome or global expression profiling. Further investigation in these genes and pathways, and correlating them to genotypes or environmental factors for DD, may aid in further elucidation of mechanisms involved in DD pathogenesis.

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“…Bioinformatic scans of the 3'UTR of PLAP-1 were conducted using four web-based miRNA target prediction programs: miRanda, PICTAR 4, PITA and TargetScan (22)(23)(24)(25)(26)(27)(28)(29)(30). miRNAs were selected based on their targeted prediction by the four programs, conservation of the binding region and the strength of the predicted interaction.…”

Section: Methodsmentioning

confidence: 99%

miR-21 and miR-101 regulate PLAP-1 expression in periodontal ligament cells

Yue

et al. 2012

Mol Med Report

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Abstract. Periodontal ligament-associated protein-1 (PLAP-1/ asporin) is a special marker in periodontal ligament tissue. It is an important regulator of osteogenic differentiation of periodontal ligament cells (PDLCs). This marker is also a prerequisite for periodontal ligament development and mineralization in maintaining homeostasis of the periodontium. However, the molecular mechanisms of the regulation of PLAP-1 expression at the post-transcriptional level remain unknown. By contrast, microRNAs (miRNAs) provide an additional level of regulation beyond that of transcription factors via regulation of the post-transcriptional control of gene expression. This study was designed to analyze miRNA differential expression patterns of PDLCs at various osteoblastic differentiation stages and to determine the contribution of miRNAs in the regulation of PLAP-1 expression during osteoblast differentiation. Bioinformatic analysis was performed to predict miRNAs that potentially regulate the gene expression of PLAP-1. Dual luciferase reporter assay and qRT-PCR were performed to confirm the effects of these miRNAs on PLAP-1 gene expression. Our results indicated that mir-101 and mir-21 target PLAP-1 to regulate its expression during osteogenic differentiation of PDLCs. IntroductionPeriodontal ligament (PDL), the most important tissue influencing the lifespan of the human tooth, is composed of heterogeneous cell populations including osteoblasts, which have osteogenic differentiation potential (1-3). Osteogenesis of periodontal ligament cells (PDLCs) is part of an important process of cytodifferentiation and mineralization to form mineralized tissue cells (4). Osteoblast differentiation results in the expression of tissue-specific gene products that form and regulate the structure of the mineralized PDL extracellular matrix (5).Periodontal ligament associated protein-1 (PLAP-1/ asporin), a specific marker of the PDL, is an important negative regulator of osteogenic differentiation in maintaining the homeostasis of periodontium (6-8). PLAP-1 was first identified as a novel member of the small leucine-rich repeat proteoglycan (SLRP) family and confirmed to be expressed specifically and predominantly in the PDL (9-10). PLAP-1 was found to be closely associated with the process of cytodifferentiation of PDL cells (11). Therefore, the relative expression level of PLAP-1 may be regarded as a specific marker for the osteogenic differentiation of PDLCs.Moreover, PLAP-1 was not only expressed specifically in the PDL of an erupted tooth but also in the dental follicle, which is the progenitor tissue of the PDL during tooth development (8). This result suggests that PLAP-1 may be involved in PDL development and cytodifferentiation (11).Furthermore, it is important to understand the processes that regulate the mineralization of PDLCs. Previous studies showed that the osteogenesis of PDLCs, a complex process in which multiple signaling pathways are involved, is regulated by numerous growth and transcription factors (12-14). However, the...

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Inferring causative variants in microRNA target sites

Cited by 65 publications

References 37 publications

A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer

A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer

Whole genome and global expression profiling of Dupuytren's disease: systematic review of current findings and future perspectives

miR-21 and miR-101 regulate PLAP-1 expression in periodontal ligament cells

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