PRKCE non-coding variants influence on transcription as well as translation of its gene

Khan, Khushbukhat; Zafar, Sameen; Hafeez, Amna; Badshah, Yasmin; Shahid, Kanza; Ashraf, Naeem Mahmood; Shabbir, Maria

doi:10.1080/15476286.2022.2139110

Cited by 7 publications

(3 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The rs11573156 SNP is located in the 5’ untranslated region (5’-UTR) of the PLA2G2A gene, acting as a TF binding site that regulates mRNA expression [37]. The current study revealed this region containing rs11573156 is a crucial SP1 binding site that modulates PLA2G2A transcript levels.…”

Section: Discussionmentioning

confidence: 77%

Identification of an allele-specific transcription factor binding interaction that regulatesPLA2G2Agene expression

Hara,

Lu,

Johnstone

et al. 2023

Preprint

View full text Add to dashboard Cite

The secreted phospholipase A2(sPLA2) isoform, sPLA2-IIA, has been implicated in a variety of diseases and conditions, including bacteremia, cardiovascular disease, COVID-19, sepsis, adult respiratory distress syndrome, and certain cancers. Given its significant role in these conditions, understanding the regulatory mechanisms impacting its levels is crucial. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs), including rs11573156, that are associated with circulating levels of sPLA2-IIA. Through Genotype-Tissue Expression (GTEx), 234 expression quantitative trait loci (eQTLs) were identified for the gene that encodes for sPLA2-IIA,PLA2G2A. SNP2TFBS (https://ccg.epfl.ch/snp2tfbs/) was utilized to ascertain the binding affinities between transcription factors (TFs) to both the reference and alternative alleles of identified SNPs. Subsequently, ChIP-seq peaks highlighted the TF combinations that specifically bind to the SNP, rs11573156. SP1 emerged as a significant TF/SNP pair in liver cells, with rs11573156/SP1 interaction being most prominent in liver, prostate, ovary, and adipose tissues. Further analysis revealed that the upregulation of PLA2G2A transcript levels through the rs11573156 variant was affected by tissue SP1 protein levels. By leveraging an ordinary differential equation, structured upon Michaelis-Menten enzyme kinetics assumptions, we modeled the PLA2G2A transcription’s dependence on SP1 protein levels, incorporating the SNP’s influence. Collectively, these data strongly suggest that the binding affinity differences of SP1 for the different rs11573156 alleles can influencePLA2G2Aexpression. This, in turn, can modulate sPLA2-IIA levels, impacting a wide range of human diseases.

show abstract

Section: Discussionmentioning

confidence: 77%

Identification of an allele-specific transcription factor binding interaction that regulatesPLA2G2Agene expression

Hara,

Lu,

Johnstone

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In the case of cancer non-coding SNPs, localization within the UTRs is considered to be especially damaging. The identified variations in these regions are found to perturb the structure of miRNA and thereby the interactions with other miRNAs and gene products [34][35][36]. UTRs maintain post-translation regulation in gene expression, any variation in the UTR region can be linked to severe pathologies [37,38].…”

Section: Discussionmentioning

confidence: 99%

Investigation of UTR Variants by Computational Approaches Reveal Their Functional Significance in PRKCI Gene Regulation

Shah

Khan

Badshah

et al. 2023

Genes

Self Cite

View full text Add to dashboard Cite

Single nucleotide polymorphisms (SNPs) are associated with many diseases including neurological disorders, heart diseases, diabetes, and different types of cancers. In the context of cancer, the variations within non-coding regions, including UTRs, have gained utmost importance. In gene expression, translational regulation is as important as transcriptional regulation for the normal functioning of cells; modification in normal functions can be associated with the pathophysiology of many diseases. UTR-localized SNPs in the PRKCI gene were evaluated using the PolymiRTS, miRNASNP, and MicroSNIper for association with miRNAs. Furthermore, the SNPs were subjected to analysis using GTEx, RNAfold, and PROMO. The genetic intolerance to functional variation was checked through GeneCards. Out of 713 SNPs, a total of thirty-one UTR SNPs (three in 3′ UTR region and twenty-nine in 5′ UTR region) were marked as ≤2b by RegulomeDB. The associations of 23 SNPs with miRNAs were found. Two SNPs, rs140672226 and rs2650220, were significantly linked with expression in the stomach and esophagus mucosa. The 3′ UTR SNPs rs1447651774 and rs115170199 and the 5′ UTR region variants rs778557075, rs968409340, and 750297755 were predicted to destabilize the mRNA structure with substantial change in free energy (∆G). Seventeen variants were predicted to have linkage disequilibrium with various diseases. The SNP rs542458816 in 5′ UTR was predicted to put maximum influence on transcription factor binding sites. Gene damage index(GDI) and loss of function (o:e) ratio values for PRKCI suggested that the gene is not tolerant to loss of function variants. Our results highlight the effects of 3′ and 5′ UTR SNP on miRNA, transcription and translation of PRKCI. These analyses suggest that these SNPs can have substantial functional importance in the PRKCI gene. Future experimental validation could provide further basis for the diagnosis and therapeutics of various diseases.

show abstract

“…However, genotype association studies for other PKC isoforms with cancer susceptibility have been conducted, indicating the pathogenic effect of certain SNPs [19,20]. Recently, the pathogenic SNPs in PKCε were also predicted through bioinformatics tools that indicated its missence SNPs pathogenicity and potential impact on the structure and function of PKCε protein and non-coding variants impact on the gene expression of the protein [21,22].…”

Section: Introductionmentioning

confidence: 99%

Elucidating the role of missense SNP of protein kinase C epsilon in HCV-induced hepatocellular carcinoma

et al. 2023

Self Cite

View full text Add to dashboard Cite

Background The protein kinase C (PKC) family of serine/threonine kinases contains more than ten isozymes that are involved in multiple signaling pathways, including cell cycle regulation and carcinogenesis. The PKCε isozyme is an oncogene known to be upregulated in various signaling pathways involved in hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC). However, there is no known association of missense SNPs in PKCε with this disease, which can be a potential biomarker for early diagnosis and treatment. This research reveals a novel missense SNP in PKCε that is associated with HCV-induced HCC in the Pakistani population. Methods The PKCε SNP with amino acid substitution of E14K was chosen for wet lab analysis. Tetra ARMS-PCR was employed for the identification of high-risk SNP in PKCε of HCV-induced HCC patients. Liver function testing was also performed for comparison between the liver condition of the HCC patient and control group, and the viral load of HCC patient samples was evaluated to determine any alteration in the viral infectivity between different genotypes of the selected high-risk PKCε variant SNP. Results Frequency distribution of the homozygous GG genotype was found to be highest among HCV-induced HCC patients and was also found to be significantly associated with disease development and progression. The p values of comparative data obtained for the other two genotypes, heterozygous AG and homozygous AA, of the SNP also showed the significance of the data for these alleles. Still, their odds ratio and relative risk analysis did not indicate their association with HCV-induced HCC. Conclusion The distribution of a genotype GG of PKCε has been found in HCV- induced HCC patients. Therefore, these PKCε SNP have the potential to be biomarkers for HCV-induced HCC. Further investigation using a larger sample size would provide additional insight into these initial data and open a new avenue for a better prognosis of this disease.

show abstract

PRKCE non-coding variants influence on transcription as well as translation of its gene

Cited by 7 publications

References 88 publications

Identification of an allele-specific transcription factor binding interaction that regulatesPLA2G2Agene expression

Identification of an allele-specific transcription factor binding interaction that regulatesPLA2G2Agene expression

Investigation of UTR Variants by Computational Approaches Reveal Their Functional Significance in PRKCI Gene Regulation

Elucidating the role of missense SNP of protein kinase C epsilon in HCV-induced hepatocellular carcinoma

Contact Info

Product

Resources

About