Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan.
School of Biochemistry & Biotechnology, University of the Punjab, Lahore, Pakistan.
RNA Biol. 2022 Jan;19(1):1115-1129. doi: 10.1080/15476286.2022.2139110.
Untranslated regions of the gene play a crucial role in gene expression regulation at mRNA and protein levels. Mutations at UTRs impact expression by altering transcription factor binding, transcriptional/translational efficacy, miRNA-mediated gene regulation, mRNA secondary structure, ribosomal translocation, and stability. PKCε, a serine/threonine kinase, is aberrantly expressed in numerous diseases such as cardiovascular disorders, neurological disorders, and cancers; its probable cause is unknown. Therefore, in the current study, the influence of PRKCE 5'-and 3'UTR variants was explored for their potential impact on its transcription and translation through several bioinformatics approaches. UTR variants data was obtained through different databases and initially evaluated for their regulatory function. Variants with regulatory function were then studied for their effect on PRKCE binding with transcription factors (TF) and miRNAs, as well as their impact on mRNA secondary structure. Study outcomes indicated the regulatory function of 73 5'UTR and 17 3'UTR variants out of 376. 5'UTR variants introduced AP1 binding sites and promoted the PRKCE transcription. Four 3'UTR variants introduced a circular secondary structure, increasing PRKCE translational efficacy. A region in 5'UTR position 45,651,564 to 45,651,644 was found where variants readily influenced the miRNA-PRKCE mRNA binding. The study further highlighted a PKCε-regulated feedback loop mechanism that induces the activity of TFs, promoting its gene transcription. The study provides foundations for experimentation to understand these variants' role in diseases. These variants can also serve as the genetic markers for different diseases' diagnoses after validation at the cell and population levels.
基因的非翻译区在 mRNA 和蛋白质水平的基因表达调控中起着至关重要的作用。UTR 中的突变通过改变转录因子结合、转录/翻译效率、miRNA 介导的基因调控、mRNA 二级结构、核糖体易位和稳定性来影响表达。蛋白激酶 Cε（PKCε）是一种丝氨酸/苏氨酸激酶，在许多疾病中异常表达，如心血管疾病、神经退行性疾病和癌症；其可能的原因尚不清楚。因此，在本研究中，通过几种生物信息学方法探索了 PRKCE 5'和 3'UTR 变异体对其转录和翻译的潜在影响。通过不同的数据库获得 UTR 变异体数据，并初步评估其调控功能。具有调控功能的变异体随后研究其对 PRKCE 与转录因子（TF）和 miRNA 结合的影响，以及对 mRNA 二级结构的影响。研究结果表明，在 376 个变体中，有 73 个 5'UTR 和 17 个 3'UTR 变体具有调控功能。5'UTR 变体引入了 AP1 结合位点，促进了 PRKCE 的转录。4 个 3'UTR 变体引入了一个环状二级结构，提高了 PRKCE 的翻译效率。在 5'UTR 位置 45651564 到 45651644 处发现了一个区域，其中变体容易影响 miRNA-PRKCE mRNA 结合。该研究进一步强调了一种 PKCε 调节的反馈环机制，该机制诱导 TF 的活性，促进其基因转录。该研究为进一步了解这些变体在疾病中的作用提供了实验基础。这些变体也可以作为不同疾病在细胞和群体水平验证后的诊断的遗传标记。
