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In Silco Study of MIR-124-1 Transcription Factors in Glioblastoma

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In Silco Study of MIR-124-1 Transcription Factors in Glioblastoma Journal of Pharmaceutical Research International 33(12): 71-83, 2021; Article no.JPRI.65792 ISSN: 2456-9119 (Past name: British Journal of Pharmaceutical Research, Past ISSN: 2231-2919, NLM ID: 101631759) In Silco Study of MIR-124-1 Transcription Factors in Glioblastoma Khloud M. Algothmi1* 1Department of Biology, King Abdulaziz University, Jedda, Saudi Arabia. Author’s contribution The sole author designed, analysed, interpreted and prepared the manuscript. Article Information DOI: 10.9734/JPRI/2021/v33i1231257 Editor(s): (1) Dr. Arun Singh, Rohilkhand Medical College and Hospital, India. Reviewers: (1) Dewa Putu Wisnu Wardhana, Udayana University, Indonesia. (2) Xiaodong Li, The Third Affiliated Hospital of Soochow University, P. R. China. Complete Peer review History: http://www.sdiarticle4.com/review-history/65792 Received 20 December 2020 Original Research Article Accepted 23 February 2021 Published 17 March 2021 ABSTRACT MIR-124-1 is a brain-abundant MIRNA, whose expression is important for neuronal tissue division, growth and actions. However, expression of miR-124-1 regulatory mechanisms controlling its actions in neuronal cells in health and diseases still poorly addressed. To understand mechanism for transcriptional and functional regulation of miR-124 in neuronal and glioblastoma cells, this study combined gene expression profiling data and computational transcription factor and microRNA target predictions. The present research focuses on transcription factors and DNA methylation, which are central to miR-124-1 expression regulation. A core promoter sequence of miR-124-1 was predicted to be 500 bp and 100 bp, upstream and downstream of its transcription start sites. Seventy three binding sites of fifty transcription factors in promoter region were found, using MatInspector software. Among these transcription factors, MEIS1, POU3F2, SALL2, ETV1, and MAZ, are known to be brain-enriched transcriptional activators. By using omics data analysis, expression of MAZ, PLAG1 KLF2 as well as a transcriptional repressor ZNF239 showed significant correlation with decline in miR-124-1 expression in glioblastoma cells. Furthermore, a potential CpG island was reported in the promoter, providing another mechanism for transcriptional inhibition of miR-124. As miR-124-1 regulates a number of neuronal physiological and pathological processes, we made an attempt to define its potential targets. A computational prediction of miR- 124-1 targets suggested 265 targets with two or more conserved seed sites. Pathway-based analysis of these target genes revealed a significant enrichment for axonal guidance and cancer signaling pathways. At least ten of these targets, SRGAP1, GNAI3, PLXNA3, SEMA5A, SEMA6A, CEBPA, CBL, RASSF5, MITF, and RPS6KB1, showed expected inverse correlation between their _____________________________________________________________________________________________________ *Corresponding author: E-mail: [email protected]; Algothmi; JPRI, 33(12): 71-83, 2021; Article no.JPRI.65792 expression values and miR-124-1 suppression in glioblastoma cells. Taken together, our data form foundation of subsequent future validation researches for miR-124-1 expression regulation including transcription factors and CpG Island within its promoter as well as functional regulation comprising biological pathways controlled by its target genes. Keywords: Bioinformatics; CpG islands; DNA methylation; glioblastoma; miR-124; neurons; promoter; transcriptional factor. 1. INTRODUCTION Understanding miRNAs' expression manners and identifying miRNA profiles can help as Transcription is regulated by protein factors and biomarkers for the diagnosis and prognosis of small RNA molecules, microRNAs (miRNAs). target treatments had begun to unfold. Notably, These micromolecules are a group of the deletion of only a single miR-124 gene, miR- evolutionarily conserved small non-coding RNAs 124-1, in the Mus musculus led to a significant (ncRNA) with a length of about ~19-23 defect in neuronal developmental processes nucleotides. A single miRNA can regulate such as smaller brain size and axonal distribution hundreds of gene expression at the post- neuronal apoptosis[13]. The molecular translational level leading to translational mechanism behind the exceptionally high level of inhibition of destruction of target mRNAs. The miR-124-1 expression in neuronal cells is still simultaneous regulation of several genes by a unclear. Few studies showed that single miRNA changes biological processes and hypermethylation is associated with cells' physiological activities [1]. microRNA-124 transcriptional silencing of miR-124-1 in human (miR-124) is encoded by three different genes cancers, including colon and hematopoietic (miR-124-1, miR-124-2, and miR-124-3) in all malignancies [14,15,16]. Besides the vertebrates. miR-124-3 resides on chromosome transcriptional regulation, the functional nature of 20, and the other two are on chromosome 8 in miR-124-1 as a negative regulator of its target the human genome. Though primary transcripts genes has been reported and linked to of miR-124 genes (pri-miRNAs) are non- neurological functions and disorders (Review in homologous, mature miR-124 sequences are [8]). However, it is still challenging to understand identical and conserved from worm to human. its functional regulation, given the existence of miR-124 is uniquely expressed in nervous tissue many potential target genes for any miRNA. This and its levels about 100 fold higher than other is the first work to investigate the regulation non-nervous tissues[2,3]. So, the primary role of mechanism of miR-124-1 transcription in miR-124 is to participate in neuronal neuronal cells to the best of our knowledge. The differentiation, development, and biological study addressed two central questions: Whether functions of the brain. Also, miR-124 stimulates brain-enriched transcription factors have binding neuron outgrowth during neurogenesis and sites in the proximal promoter of miR-124-1, and contributes to converting human fibroblasts into whether there are more potential locations of neurons [4,5,6,7]. Furthermore, the association methylation may affect miR-124-1 gene between the aberrant expression of miR-124 and transcription. neurological disorders, as neurodegenerative and neuroimmune diseases, oxidative stress, 2. METHODS stroke, and cancer, was reported previously (Reviewed in [8]). Several studies revealed 2.1 The Sequence of MIR-124 significant down-regulation of miR-124 in various brain tumors like glioblastoma and MIR-124-1 and miR-124-2 are intergenic medulloblastoma [9,10]. miRNAs located on human chromosome 8 ranging from 9903388 to 9903472 bp and from Moreover, its reduction level in 64379149 to 64379257 bp, respectively. MIR- neurodegenerative diseases such as Alzheimer's 124-3 is located on chromosome 20 ranging from disease (AD) and Parkinson's disease (PD) was 63178500 to 63178586 bp. The precursor also reported [11,12]. Therefore, miR-124 had sequences were retrieved from miRBase been proposed as a diagnostic and prognostic (http://www.mirbase.org) and aligned using Basic marker and a therapeutical target for neurological Local Alignment Search Tool (BLAST) disorders as brain tumors, neurodegenerative (https://blast.ncbi.nlm.nih.gov/Blast.cgi). disorders, and stroke (Reviewed in [8]). 72 Algothmi; JPRI, 33(12): 71-83, 2021; Article no.JPRI.65792 2.2 The Sequence of MIR-124 Promoters visualization of the metabolic pathways collected KEGG database. Fisher’s exact test was applied The promoter sequences of miR-124-1 and miR- to discriminate if those genes are enriched in the 124-2 were obtained using the GenBank, KEGG pathway. P-value < 0.05 cut off was Nucleotide database, National Center for chosen to determine the significant level of Biotechnology Information (NCBI). DNA pathways. methylation analysis and potential transcription factor binding sites were predicted using the 3. RESULTS MethPrimer and MatInspector programs. 3.1 Low Conservation between Human 2.3 Meth Primer MIR-124-1 Promoter and MIR-124-2 Promoter Regions CpG islands were predicted across miR-124-1 promoter sequence using the default settings of The precursor sequences of human miR-124-1, the MethPrimer program [17] miR-124-2, and miR-124-3 were extracted from (http://www.urogene.org/methprimer/). The the NCBI database (June 2016), alignments default settings are: reveal high conservation among them (~89%) (Fig.1). However, mature sequences of miR-124- 1. The promoter comprises a DNA sequence 5p and miR-124-3p are 100% conserved of at least 200bp in length between all three precursors. The pri-miRNA 2. CG content in the promoter is over 50% containing the pre-miR-124-2 is known as miR- 3. The ratio of observed to expect the number 124-2 host gene (miR-124-2HG), whereas the of CG dinucleotides is over 0.6 pre-miR-124-1 appears to be derived from annotated long intergenic non-protein coding 2.4 Genomatix MatInspector RNA 599 (LINC00599). As the promoter sequence of miR-124-1 and miR-124-2 are not Genomatix MatInspector prediction search characterized yet, the genomic sequences were (http://www.genomatix.de/) for transcription factor obtained from GenBank in June 2016 (Supp. 1A, binding sites (TFBSs), several parameters B). The host transcript of pre-miR-124-3 has not include the core and matrix similarities, which are been annotated yet; therefore, it is excluded from calculated within MatInspector [18]. The core our work. The sequence comparison of human similarity was set to 1 and >0.95 for
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