Incomplete penetrance and variable expressivity: is there a microRNA connection?

Ahluwalia, Jasmine K; Hariharan, Manoj; Bargaje, Rhishikesh; Pillai, Beena; Brahmachari, Vani

doi:10.1002/bies.200900066

Cited by 29 publications

(35 citation statements)

References 77 publications

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“…10 We showed that a significantly high number of IP-VE genes are targeted by multiple miRNAs and are co-expressed with the cognate miRNA in the same tissue. Meta-analysis of data from the public domain indicates a negative correlation between the miRNA and target protein levels.…”

Section: Introductionmentioning

confidence: 88%

“…Meta-analysis of data from the public domain indicates a negative correlation between the miRNA and target protein levels. 10 Our analysis indicated that SNP in the miRNA target site can potentially affect its interaction with miRNA based on the predictions using dbSMR database, which utilizes structural parameters associated with variation. 16 For our current study, we selected 2 IP-VE genes-namely, JAG1 and TGFBR2-from a list of 88 genes previously predicted as targets of miRNA mediated regulation.…”

Section: Introductionmentioning

confidence: 96%

“…8,9 We have earlier proposed a model for the mechanism of IP-VE invoking microRNA (miRNA) in differential regulation of homologous alleles independent of the primary disease causing mutation. 10 MiRNAs have emerged as one of the major post-transcriptional regulators of gene expression. The interaction of miRNA with target site, even with partial complementarity, offers immense scope for variation in kinetics of miRNA and target interaction and the resultant dynamics in gene expression providing specificity and variability at the same time.…”

Section: Introductionmentioning

confidence: 99%

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Modeling SNP mediated differential targeting of homologous 3′UTR by microRNA

et al. 2012

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We had previously proposed that the post-transcriptional regulation through microRNA as a mechanism for incomplete penetrance and variable expressivity, leads to lack of correlation between genotype and phenotype. Here we report the validation of miRNA-target interactions we predicted earlier and demonstrate the regulation of endogenous JAG1 by hsamiR-214 and hsa-miR-124, and TGFBR2 by hsa-miR-34b*, through luciferase activity of reporter constructs and also the expression levels of the endogenous genes. Using these targets, we have modeled the diploid state for miRNA target site with heterozygosity for the SNP and demonstrate the differential targeting of an otherwise identical 3'UTR. We show that SNP rs8708 (A . G) at the target site of hsa-miR-214 can relieve the repression while an SNP rs11466532 (C . T) enhances the repression of reporter expression by hsa-miR-34b*. We discuss the results in the light of its implications in the context of penetrance of dominant mutations in miRNA targeted genes, using JAG1 as an example. These observations imply that disease causing mutations in JAG1 linked to the SNP rs8708G will be poorly targeted by hsa-miR-214 when present against a normal allele of JAG1 with rs8708A and will show penetrance of JAG1 mutations as Alagille syndrome, while mutant JAG1 linked to rs8708A against rs8708G on the normal allele will show either no disease or much attenuated symptoms and hence exhibit incomplete penetrance.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Modeling SNP mediated differential targeting of homologous 3′UTR by microRNA

et al. 2012

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“…When the SNP locus is in the 'seed' region of a miRNA, the stability of the mRNA-miRNA interaction may be altered by this polymorphism. 27 RNAhybrid (http://bibiserv. techfak.uni-bielefeld.de/rnahybrid) predicts the secondary structure and minimum free energy (MFE) of the entire micro-RNA:mRNA duplex.…”

Section: Selection Of Snps In the Mirna Target Site Of Scrc-related Gmentioning

confidence: 99%

The screening of the functional microRNA binding site SNPs in sporadic colorectal cancer genes

Lei

Chen

et al. 2017

Cancer Biology & Therapy

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Sporadic colorectal cancer (sCRC) is one of the most commonly diagnosed cancers worldwide, but few genetic markers have been identified and used for its early detection. MicroRNAs are diverse cellular regulators in cancer pathogenesis that bind to the 3 0 -untranslated region (3 0 -UTR) of their target mRNAs, and variants within the miRNA target sites on sCRC-related genes may influence its pathogenesis. To investigate this possibility, we used a bioinformatical method to screen SNPs for putative changes in miRNA recognition sites within the 3 0 -UTR of sCRC-related genes. The rs11466537 single nucleotide polymorphism was predicted to modify the regulation of hsa-miR-1193 on the Transforming Growth Factor b Receptor II (TGFBR2) gene. Additionally, luciferase reporter assays indicated that hsa-miR-1193 bound the T allele more strongly than the A allele of rs11466537 (with A being the less frequent variant), and real time-polymerase chain reaction and western blot analysis showed that TGFBR2 is significantly repressed by hsa-miR-1193. Furthermore, overexpression of hsa-miR-1193 promoted HT-29 cell proliferation, while the loss of hsa-miR-1193 inhibited the process. Finally, the rs11466537 genotyping result revealed that the frequency of A allele carriers was 1.5% in the control blood samples, but 0 in the sCRC patients' normal colon tissue samples. Our results demonstrated that hsa-miR-1193 may be involved in sCRC tumourigenesis at least in part by suppression of TGFBR2, and the A allele of rs11466537 disturbed the regulation of hsa-miR-1193 on TGFBR2.

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“…The pre-microRNA is then transported out of the nucleus to the cytoplasm by the nuclear export complex composed of Exportin 5 and RAN. In the cytoplasm, the Dicer complex further cuts the pre-microRNA into its mature form; the mature microRNA is functional as part of the RISC (Ryan et al 2010;Ahluwalia et al 2009). …”

Section: Microrna Biogenesismentioning

confidence: 99%

Towards identifying New Human Ribonucleases that Cleave microRNA Using a High-Throughput Method.

Ye¹

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Incomplete penetrance and variable expressivity: is there a microRNA connection?

Cited by 29 publications

References 77 publications

Modeling SNP mediated differential targeting of homologous 3′UTR by microRNA

Modeling SNP mediated differential targeting of homologous 3′UTR by microRNA

The screening of the functional microRNA binding site SNPs in sporadic colorectal cancer genes

Towards identifying New Human Ribonucleases that Cleave microRNA Using a High-Throughput Method.

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