Abstract
Variants in regulatory regions are predicted to play an important role in disease susceptibility of common diseases. Polymorphisms mapping to microRNA (miRNA) binding sites have been shown to disrupt the ability of miRNAs to target genes resulting in differential mRNA and protein expression. Skin tumor susceptibility 5 (Skts5) was identified as a locus conferring susceptibility to chemically-induced skin cancer in NIH/Ola by SPRET/Outbred F1 backcrosses. To determine if polymorphisms between the strains which mapped to putative miRNA binding sites in the 3′ untranslated region (3′UTR) of genes at Skts5 influenced expression, we conducted a systematic evaluation of 3′UTRs of candidate genes across this locus. Nine genes had polymorphisms in their 3′UTRs which fit the linkage data and eight of these contained polymorphisms suspected to interfere with or introduce miRNA binding. 3′UTRs of six genes, Bcap29, Dgkb, Hbp1, Pik3cg, Twistnb, and Tspan13 differentially affected luciferase expression, but did not appear to be differentially regulated by the evaluated miRNAs predicted to bind to only one of the two isoforms. 3′UTRs from four additional genes chosen from the locus that fit less stringent criteria were evaluated. Ifrd1 and Etv1 showed differences and contained polymorphisms predicted to disrupt or create miRNA binding sites but showed no difference in regulation by the miRNAs tested. In summary, multiple 3′UTRs with putative functional variants between susceptible and resistant strains of mice influenced differential expression independent of predicted miRNA binding.
Highlights
Mus spretus mice are resistant to skin cancer compared to Mus musculus mice
We further evaluated 39 untranslated region (39UTR) from four additional genes that contained polymorphisms observed in SPRET/Outbred and SPRET/EiJ but not in STF/PAS and identified two 39UTRs, Etv1 and Ifrd1 that showed differential lucifierase expression between SPRET and NIH/Ola but exhibited no differences in expression with predicted miRNAs
These results indicate that variants in 39UTRs can affect expression in vitro and that observed differential mRNA expression of Hbp1, Tspan13, Pik3cg, Bcap29 and Twistnb between NIH/Ola and SPRET/Outbred and of Etv1 and Ifrd1 between NIH/Ola and SPRET/Outbred-SPRET/EiJ may be due to variants in the 39UTR
Summary
In previous linkage studies of dimethylbenz [a]. Anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)- induced skin cancer a number of skin cancer susceptibility loci were identified in SPRET/Outbred by NIH/Ola F1 backcross mice [1,2,3,4]. SPRET/EiJ by FVB/N, SPRET/EiJ by NIH/Ola and STF/Pas by NIH/Ola F1 backcross mice which identified additional susceptibility loci. One of the skin susceptibility loci, Skin tumor susceptibility 5 (Skts5), was found in the SPRET/Outbred by NIH/. But not in STF/Pas by NIH/Ola F1 or SPRET/EiJ by FVB/N crosses [3,4]. Sequence analyses of 54 genes and coding elements across a 14-Mb peak linkage region at Skts led to the identification of a number of coding changes consistent with the linkage analyses (Mahler et al 2008)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
