The SNPs within 3'UTR of miRNA Target Genes Related to Multiple Sclerosis: A Computational Prediction

2020 ◽  
Vol 17 (2) ◽  
pp. 133-147
Author(s):  
Mina Zafarpiran ◽  
Roya Sharifi ◽  
Zeinab Shirvani-Farsani
Keyword(s):  
Multiple Sclerosis ◽  
Gene Regulation ◽  
Binding Sites ◽  
Target Genes ◽  
Demyelinating Disease ◽  
Target Prediction ◽  
Computational Prediction ◽  
Functional Verification ◽  
Candidate Snps ◽  
Inflammatory Genes

Background: Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system, and genetic factors play an important role in its susceptibility. The expressions of many inflammatory genes implicated in MS are regulated by microRNA (miRNAs), whose function is to suppress the translation by pairing with miRNA Recognition Elements (MREs) present in the 3' untranslated region (3'UTR) of target mRNA. Recently, it has been shown that the Single Nucleotide Polymorphism (SNPs) present within the 3'UTR of mRNAs can affect the miRNA-mediated gene regulation and susceptibility to a variety of human diseases. Objective: The aim of this study was to analyze the SNPs within the 3'UTR of miRNA inflammatory target genes related to multiple sclerosis. Methods: By DisGeNET, dbGaP, Ovid, DAVID, Web of knowledge, and SNPs databases, 3'UTR genetic variants were identified in all inflammatory genes associated with MS. Also, miRNA's target prediction databases were used for predicting the miRNA binding sites. Results: We identified 125 SNPs with MAF>0.05 located in the binding site of the miRNA of 35 genes among 59 inflammatory genes related to MS. Bioinformatics analysis predicted 62 MRE-modulating SNPs and 59 MRE-creating SNPs in the 3'UTR of MSimplicated inflammatory genes. These candidate SNPs within miRNA binding sites of inflammatory genes can alter the miRNAs binding, and consequently lead to the mRNA gene regulation. Conclusion: Therefore, these miRNA and MRE-SNPs may play important roles in personalized medicine of MS, and hence, they would be valuable for further functional verification investigations.

scholarly journals The Computational Analysis Conducted on miRNA Target Sites in Association with SNPs at 3’UTR of ADHD-implicated Genes

2020 ◽  
Vol 20 (1) ◽  
pp. 58-75
Author(s):  
Adel Abdi ◽  
Mina Zafarpiran ◽  
Zeinab S. Farsani
Keyword(s):  
Binding Sites ◽  
Mirna Target ◽  
Target Genes ◽  
Target Prediction ◽  
Functional Verification ◽  
Candidate Snps ◽  
Epigenetic Factors ◽  
Hyperactivity Disorder ◽  
Mrna Gene ◽  
Recognition Elements

Background: Attention-deficit/hyperactivity disorder (ADHD) is a frequent chronic neuropsychiatric disorder in which different factors including environmental, genetic, and epigenetic factors play an important role in its pathogenesis. One of the effective epigenetic factors is recognized as MicroRNAs (miRNAs). On the other hand, it has been indicated that the single nucleotide polymorphism (SNPs) present within 3'UTR (3' untranslated region) of mRNAs can influence the regulation of miRNA-mediated gene and susceptibility to a diversity of human diseases. Methods: The purpose of this study was to analyze the SNPs within the 3'UTR of miRNA target genes associated with ADHD. 3'UTR genetic variants were identified in all genes associated with ADHD using DisGeNET, dbGaP, Ovid, DAVID, Web of knowledge, and SNPs databases. miRNA's target prediction databases were applied in order to predict the miRNA binding sites. 124 SNPs with MAF>0.05 were identified located in the binding site of the miRNA of 35 genes amongst 51 genes associated with ADHD. Results: Bioinformatics analysis predicted 81 MRE (miRNA recognition elements)-creating SNPs, 101 MRE-breaking SNPs, 61 MRE-enhancing SNPs, and finally predicted 41 MREdecreasing SNPs in the 3'UTR of ADHD-implicated genes. These candidate SNPs within these genes miRNA binding sites can alter the miRNAs binding, and consequently, lead to mRNA gene regulation. Conclusion: Therefore, these miRNA and MRE-SNPs may play important roles in ADHD, and because of that, they would be valuable for further investigation in the field of functional verification.

scholarly journals tRFtarget: a database for transfer RNA-derived fragment targets

2020 ◽  
Vol 49 (D1) ◽  
pp. D254-D260 ◽  
Author(s):  
Ningshan Li ◽  
Nayang Shan ◽  
Lingeng Lu ◽  
Zuoheng Wang
Keyword(s):  
Binding Sites ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Target Prediction ◽  
Transfer Rna ◽  
Web Based ◽  
New Class ◽  
Physiological Processes ◽  
Graphic Illustration ◽  
Functional Pathway

Abstract Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs and play important roles in biological and physiological processes. Prediction of tRF target genes and binding sites is crucial in understanding the biological functions of tRFs in the molecular mechanisms of human diseases. We developed a publicly accessible web-based database, tRFtarget (http://trftarget.net), for tRF target prediction. It contains the computationally predicted interactions between tRFs and mRNA transcripts using the two state-of-the-art prediction tools RNAhybrid and IntaRNA, including location of the binding sites on the target, the binding region, and free energy of the binding stability with graphic illustration. tRFtarget covers 936 tRFs and 135 thousand predicted targets in eight species. It allows researchers to search either target genes by tRF IDs or tRFs by gene symbols/transcript names. We also integrated the manually curated experimental evidence of the predicted interactions into the database. Furthermore, we provided a convenient link to the DAVID® web server to perform downstream functional pathway analysis and gene ontology annotation on the predicted target genes. This database provides useful information for the scientific community to experimentally validate tRF target genes and facilitate the investigation of the molecular functions and mechanisms of tRFs.

The mMiR-223: An inflammatory MicroRNA Involved in Pathogenesis of Multiple Sclerosis

2018 ◽  
Author(s):  
Saba Gharibi ◽  
Bahram Moghimi ◽  
Mohammad Taher Tahoori ◽  
Mohammad Bagher Mahmudi ◽  
Ensieh Shahvazian ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Target Genes ◽  
Demyelinating Disease ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Protein Coding ◽  
Mirna Genes ◽  
Brain And Spinal Cord ◽  
The Brain

Multiple sclerosis (MS) is the most common autoimmune inflammatory demyelinating disease that affects the brain and spinal cord. Dysregulation or mutation of miRNA genes have been linked to the pathogenesis of MS. The miRNAs are short, 20-22 nucleotide long, single-stranded regulatory and non–protein coding RNAs that modulate the expression of multiple target genes. Among miRNAs, miR-223 has been reported to play a critical role in MS. This review concentrates on the emerging role of miR-223 in inflammatory responses and specifically discusses how alterations in miR-223 expression are associated with the development of MS. This review also suggests that miR-223 can be used as a biomarker for diagnosis of MS and discovering novel therapeutics for MS treatment.

Covalent-Fragment Screening of Brd4 Identifies a Ligandable Site Orthogonal to the Acetyl-Lysine Binding Sites

2019 ◽  
Author(s):  
Michael Olp ◽  
Daniel Sprague ◽  
Stefan Kathman ◽  
Ziyang Xu ◽  
Alexandar Statsyuk ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Binding Site ◽  
Binding Sites ◽  
Computational Prediction ◽  
Chemical Probes ◽  
Computational Docking ◽  
Fragment Screening ◽  
Covalent Inhibitors ◽  
Bet Protein ◽  
Proof Of Principle

<p>Brd4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as a promising epigenetic target in cancer and inflammatory disorders. All reported BET family ligands bind within the bromodomain acetyl-lysine binding sites and competitively inhibit BET protein interaction with acetylated chromatin. Alternative chemical probes that act orthogonally to the highly-conserved acetyl-lysine binding sites may exhibit selectivity within the BET family and avoid recently reported toxicity in clinical trials of BET bromodomain inhibitors. Here, we report the first identification of a ligandable site on a bromodomain outside the acetyl-lysine binding site. Inspired by our computational prediction of hotspots adjacent to non-homologous cysteine residues within the <i>C</i>-terminal Brd4 bromodomain (Brd4-BD2), we performed a mid-throughput mass spectrometry screen to identify cysteine-reactive fragments that covalently and selectively modify Brd4. Subsequent mass spectrometry, NMR and computational docking analyses of electrophilic fragment hits revealed a novel ligandable site near Cys356 that is unique to Brd4 among all human bromodomains. This site is orthogonal to the Brd4-BD2 acetyl-lysine binding site as Cys356 modification did not impact binding of the pan-BET bromodomain inhibitor JQ1 in fluorescence polarization assays. Finally, we tethered covalent fragments to JQ1 and performed NanoBRET assays to provide proof of principle that this orthogonal site can be covalently targeted in intact human cells. Overall, we demonstrate the potential of targeting sites orthogonal to bromodomain acetyl-lysine binding sites to develop bivalent and covalent inhibitors that displace Brd4 from chromatin.</p>

Identification of BAP1-associated MicroRNAs and Implications in Cancer Development

2019 ◽  
pp. 1-4
Author(s):  
Tikam Chand ◽  
Tikam Chand
Keyword(s):  
Gene Regulation ◽  
In Silico ◽  
Mirna Target ◽  
Target Prediction ◽  
Differential Regulation ◽  
Cancer Development ◽  
Mirna Target Prediction ◽  
Cancer Types ◽  
In Silico Tools

Having role in gene regulation and silencing, miRNAs have been implicated in development and progression of a number of diseases, including cancer. Herein, I present potential miRNAs associated with BAP1 gene identified using in-silico tools such as TargetScan and Exiqon miRNA Target Prediction. I identified fifteen highly conserved miRNA (hsa-miR-423-5p, hsa-miR-3184-5p, hsa-miR-4319, hsa-miR125b-5p, hsa-miR-125a-5p, hsa-miR-6893-3p, hsa-miR-200b-3p, hsa-miR-200c-3p, hsa-miR-505-3p.1, hsa-miR-429, hsa-miR-370-3p, hsa-miR-125a-5p, hsa-miR-141-3p, hsa-miR-200a-3p, and hsa-miR-429) associated with BAP1 gene. We also predicted the differential regulation of these twelve miRNAs in different cancer types.

Gene Therapy Approaches in an Autoimmune Demyelinating Disease: Multiple Sclerosis

2020 ◽  
Vol 19 (6) ◽  
pp. 376-385
Author(s):  
Md. A. Islam ◽  
Shoumik Kundu ◽  
Rosline Hassan
Keyword(s):  
Multiple Sclerosis ◽  
Gene Therapy ◽  
Disease Progression ◽  
Demyelinating Disease ◽  
Human Subjects ◽  
Mice Model ◽  
Focal Lesions ◽  
Protective Function ◽  
Monocytes And Macrophages ◽  
Specific Symptoms

Multiple Sclerosis (MS) is the most common autoimmune demyelinating disease of the Central Nervous System (CNS). It is a multifactorial disease which develops in an immune-mediated way under the influences of both genetic and environmental factors. Demyelination is observed in the brain and spinal cord leading to neuro-axonal damage in patients with MS. Due to the infiltration of different immune cells such as T-cells, B-cells, monocytes and macrophages, focal lesions are observed in MS. Currently available medications treating MS are mainly based on two strategies; i) to ease specific symptoms or ii) to reduce disease progression. However, these medications tend to induce different adverse effects with limited therapeutic efficacy due to the protective function of the blood-brain barrier. Therefore, researchers have been working for the last four decades to discover better solutions by introducing gene therapy approaches in treating MS generally by following three strategies, i) prevention of specific symptoms, ii) halt or reverse disease progression and iii) heal CNS damage by promoting remyelination and axonal repair. In last two decades, there have been some remarkable successes of gene therapy approaches on the experimental mice model of MS - experimental autoimmune encephalomyelitis (EAE) which suggests that it is not far that the gene therapy approaches would start in human subjects ensuring the highest levels of safety and efficacy. In this review, we summarised the gene therapy approaches attempted in different animal models towards treating MS.

Computational Analysis of miRNA and their Gene Targets Significantly Involved in Colorectal Cancer Progression

MicroRNA ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 68-75 ◽  
Author(s):  
Jeyalakshmi Kandhavelu ◽  
Kumar Subramanian ◽  
Amber Khan ◽  
Aadilah Omar ◽  
Paul Ruff ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Progression ◽  
Target Prediction ◽  
Computational Prediction ◽  
Initial Step ◽  
Kegg Pathways ◽  
Candidate Mirnas ◽  
Common Cancer ◽  
Colon Cancer Progression

Background:Globally, colorectal cancer (CRC) is the third most common cancer in women and the fourth most common cancer in men. Dysregulation of small non-coding miRNAs have been correlated with colon cancer progression. Since there are increasing reports of candidate miRNAs as potential biomarkers for CRC, this makes it important to explore common miRNA biomarkers for colon cancer. As computational prediction of miRNA targets is a critical initial step in identifying miRNA: mRNA target interactions for validation, we aim here to construct a potential miRNA network and its gene targets for colon cancer from previously reported candidate miRNAs, inclusive of 10 up- and 9 down-regulated miRNAs from tissues; and 10 circulatory miRNAs. </P><P> Methods: The gene targets were predicted using DIANA-microT-CDS and TarBaseV7.0 databases. Each miRNA and its targets were analyzed further for colon cancer hotspot genes, whereupon DAVID analysis and mirPath were used for KEGG pathway analysis.Results:We have predicted 874 and 157 gene targets for tissue and serum specific miRNA candidates, respectively. The enrichment of miRNA revealed that particularly hsa-miR-424-5p, hsa-miR-96-5p, hsa-miR-1290, hsa-miR-224, hsa-miR-133a and has-miR-363-3p present possible targets for colon cancer hallmark genes, including BRAF, KRAS, EGFR, APC, amongst others. DAVID analysis of miRNA and associated gene targets revealed the KEGG pathways most related to cancer and colon cancer. Similar results were observed in mirPath analysis. A new insight gained in the colon cancer network pathway was the association of hsa-mir-133a and hsa-mir-96-5p with the PI3K-AKT signaling pathway. In the present study, target prediction shows that while hsa-mir-424-5p has an association with mostly 10 colon cancer hallmark genes, only their associations with MAP2 and CCND1 have been experimentally validated.These miRNAs and their targets require further evaluation for a better understanding of their associations, ultimately with the potential to develop novel therapeutic targets.

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