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  • It is well established that transcription

    2021-09-03

    It is well established that transcription factors are the major key players in regulating the transcriptional state of the targeted gene. 15 TFs were found in the present study, which were predicted to have the binding affinity with the EZH2 promoter region. Out of these, GCF, AP-2 and Sp1 were most abundantly distributed whereas Albumin_US2, Ig-dc, Sp1 and AP3 were found with the highest confidence of probability of finding that TFs strictly in the promoter region (Fig. 3). Earlier studies have reported TFs such as C-Myc, Myb, STAT, EIK, E2F, HIF1-α and ERα playing role in EZH2 overexpression via disruption in various pathways like MEK-ErK-1/2-EIK-1, pRB-E2F and hypoxia-induced conditions (Salvatori et al., 2011; Deb et al., 2013a, Deb et al., 2013b). These TFs were not in common with the predicted ones, while these are known to have well interaction with the predicted transcription factors viz. AP2, AP3, Sp1, NF-κβ (Lint et al., 1997; Gutterson and Reuber, 2004). The transcription factor SP1 is known to interact with C-myc and together they regulate the Mupirocin of several genes (Wilson et al., 2010; Maiques-Diaz et al., 2012; Gopisetty et al., 2013; You et al., 2014). This interaction should be explored at the next level so as to get the valid insight of EZH2 gene regulation via TFs. With the help of two databases, BioMuta and BioXpress, 6 single nucleotide variations were hauled to have an association with cancer. But not yet validated at the population level (not reported in dbSNP). The latter database gives insight about EZH2 gene overexpression in 12 types of cancers (supplementary material). There are various SNPs based association studies of EZH2 gene (Bachmann et al., 2005; Makishima et al., 2010; Yoon et al., 2010; Crea et al., 2012; Ryan et al., 2011; Je et al., 2012; Paolichhi et al., 2013; Yu et al., 2013; Ma et al., 2014; Maftouh et al., 2014; Wang et al., 2014; Yu et al., 2014; Zhou et al., 2014; Fornaro et al., 2015; Gao et al., 2015; Jung Su et al., 2015; Tao et al., 2015; Sun et al., 2016; Chang et al., 2016; Li et al., 2016; Lee et al., 2018; Ling et al., 2018; Ma et al., 2018). Even though the human EZH2 gene has a considerable number of SNPs (some having no functional effect or very low frequency), it is difficult to analyze all SNPs present in a gene for the candidate gene approach. As it remains challenging to interpret clinically important novel variants, various bioinformatics tools have been developed that predict biological consequences of these polymorphisms. These tools have been used in the present study to fish out some novel SNPs of EZH2 protein along with the prediction of the biological effect of some already studied SNPs using these tools. Thus SNPs have probably an important role in various diseases could be focused upon. Since both non-coding and coding regions are equally important. Hence, both have been studied in the present study. In silico analyses was used to identify most likely functional variants of the EZH2 gene. However, a complete picture of the functional significance of allelic variants cannot be obtained by a single bioinformatics tool. Hence a number of complementary bioinformatics tools were used to conduct the current analysis. Two ncSNP prediction tools, RegulomeDB and PolymiRTS, were used for the analysis of ncSNPs of EZH2 gene. 11 ncSNPs (rs6950683, rs17171119, rs1996996, rs73158274, rs41277434, rs3757441, rs10952783, rs2177567, rs1880357, rs73158280 and rs3217095) were prioritized with the help of these tools for disease association studies. Four composite tools SIFT, Polyphen-2, I-Mutant v3.0 and SNAP2 were applied to predict the effect of coding SNPs on protein structure and function. rs2302427 was the only cSNP found to be validated on the basis of MAF and pathogenic significance. This SNP ID was submitted as an input for the above-mentioned tools. Out of these tools SIFT, Polyphen-2 and I-Mutant v3.0 have predicted rs2302427 as effective/deleterious SNP. Out of 12 SNPs, 4 SNPs with SNP IDs: rs6950683, rs3757441, rs41277434, and rs2302427 are very well known and a plethora of literature is available regarding their association with various diseases including bladder cancer, colorectal cancer, oral cancer, gastric cancer, esophageal cancer, pancreatic cancer and cholangiocarcinoma (Crea et al., 2012, Paolichhi et al., 2013, Ma et al., 2014, Maftouh et al., 2014, Fornaro et al., 2015, Jung Su et al., 2015, Chang et al., 2016, Li et al., 2016, Lee et al., 2018, Ma et al., 2018,). rs6950683 found at the promoter region of the EZH2 gene and was found to be associated in lowering the risk of oral cancer. Functionally, this change is known to increase the methylation of the promoter region of the EZH2 gene by some unknown mechanism (Jung Su et al., 2015). So, there is a need to elucidate its biological significance with respect to the transcriptional state of the EZH2 gene. In the present study, we have found rs3217095 present at 3’UTR to be the only SNP having validated MAF. With the help of PolymiRTS this is also detected as the only rsID which is predicted to affect miRNA target site (has-miR-4779). Pursual of literature has shown that no study has been done for experimental validation of rs3217095. Hence, the present findings require to be validated experimentally.