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

Abstract

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.

miR-34 is maternally inherited in Drosophila melanogaster and Danio rerio

“…Therefore, we believe that the low penetrance of the phenotype is likely to be because of the effect of redundant pathways that can buffer the effect of individual miRNAs. Moreover, miRNAs have been previously implicated in incomplete penetrance and variable expressivity (58,59). …”

miR-200a-3p facilitates bladder cancer cell proliferation by targeting the A20 gene

“…MicroRNAs (miRNAs/miRs) are noncoding, short, single-stranded RNAs (6). Target protein expression is commonly regulated by miRNAs via binding to the 3'untranslated region (UTR) of substrates (7,8). Specific pathological features result in altered microRNA expression, which indicates oncogenic or antioncogenic properties.…”

Abiotic Stress Responsive miRNA-Target Network and Related Markers (SNP, SSR) in Brassica juncea

“…In current study, high frequency of C/T transition noted in consistent with previous study (Low et al, 2014 ; Rawlings-Goss et al, 2014 ) (Table S4A ). It has been also reported that, C/T transition at the target site enhances the repression of TGFBR2 by hsa-miR-34b * (Ahluwalia et al, 2012 ). We identified two SNPs with deleterious effect on genes encoding methyltransferase and phosphoglycerate mutase targeted by miR3434 and miR5658.…”