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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 26-31

Bioinformatics analysis of SOX2 gene expression in gliogenesis


School of Life Sciences; Department of Biotechnology; Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India

Date of Submission03-Apr-2020
Date of Acceptance12-Apr-2020
Date of Web Publication2-Jul-2020

Correspondence Address:
Mr. Shouhartha Choudhury
School of Life Sciences, Assam University, Silchar - 788 011, Assam; Department of Biotechnology, Assam University, Silchar - 788 011, Assam; Department of Life Science and Bioinformatics, Assam University, Silchar - 788 011, Assam
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_4_20

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  Abstract 


Background: Glioblastoma is the most aggressive cerebral tumor is invariable and lethal. The previous stem cell experiment reported the glioblastoma is expressed in neural cells. SOX2 gene has self-renewal ability in the neural stem cells. The SOX2 gene is a master regulator involved in sustaining self-renewal in neural stem cells. Therefore, the study of the SOX2 gene is essential to explore the aberrant growth of glioblastoma. The SOX family characterized by the DNA-binding domain (high-mobility group [HMG] domain) is involved in the developmental process in mammals.
Objective: The present study objective was to investigate the SOX family in mammals. The SOX family plays an essential role during the developmental process in mammals. Therefore, the investigation of the SOX family in the mammalian genome is now mandatory to explore the specific function of the SOX2 gene.
Methods: In this study, the author performed powerful bioinformatics and computational technique to the current knowledge of the SOX family in particular organisms.
Results: The present study findings confirmed the presence of SOX2 gene in both organisms. The author took a closer look at the SOX family and analyzed genes known so far those that have a different functional domain. The findings provide evidence of the SOX family and their HMG domain in between Homo sapiens and Mus musculus. The conserved domain, motifs, phylogeny, Chromosome location, and gene expression hypothesized that the SOX2 gene is expressed in neural stem cells.
Conclusion: The findings concluded that the SOX family is associated with the developmental process in mammals. In contrast, the SOX2 gene expression controls the proliferation of neural stem cells. The downregulated expression of SOX2 gene leads to the loss of tumorigenicity. These observations support the hierarchical model of glioblastoma controlled by SOX2 gene, which would be the ultimate target for glioblastoma therapy.

Keywords: Gliogenesis, SOX family, SOX2


How to cite this article:
Choudhury S. Bioinformatics analysis of SOX2 gene expression in gliogenesis. Int J Neurooncol 2020;3:26-31

How to cite this URL:
Choudhury S. Bioinformatics analysis of SOX2 gene expression in gliogenesis. Int J Neurooncol [serial online] 2020 [cited 2020 Aug 10];3:26-31. Available from: http://www.Internationaljneurooncology.com/text.asp?2020/3/1/26/288791




  Introduction Top


Glioblastoma is the most aggressive human cancer with 5-year survival.[1] Gliomas are the most frequent cerebral neoplasia, with glioblastoma being the most common and aggressive.[2] Despite the past hug efforts, this statistic has markedly improved over the decade. The proliferation, infiltration, and suppression of tumor immune surveillance contribute to the malignant phenotypes of glioblastoma. The glioblastoma cells deeply penetrate into the surrounding tissue and reminiscent of the ability to migrate neural cells. These hypotheses consistent in the tumor originate from neural cells. Glioma cells express the number of molecules associated with the development of neural cells.[3],[4] The reason for deficient prognosis is the inherent complexity of tumor. The cancer-initiating cells are characterized by their ability to induce tumorigenesis and self-renewal. Recent concepts of cancer suggested that the neural cells may determine the biological characteristics of brain tumors. The light of the SOX family is involved in a diverse range of development and differentiation process in mammals. The SOX family found in several mammalian genomes is characterized by DNA-binding domain (high-mobility group [HMG] domain). The shed light of the SOX2 gene appears especially due to its role in sustaining growth and self-renewal of the neural stem cell in the embryo.[5],[6],[7],[8],[9] SOX2 is considered as a master gene in mammalian embryogenesis and a complex nuclear transcription factor gene that affects pluripotency and differentiation in the embryonic stem cells.[8] SOX2 gene is expressed in neural cells, early precursor cell, and mature neurons for maintaining cell proliferative potential.[10],[11] SOX2 gene expressed in several malignant tissues and expression is highly variable in the cells, because down-regulated effect of SOX2 gene is dependent.[12],[13],[14],[15],[16] The arguments of heterogeneity in glioma cell typically contain various stages of differentiation. These previous data and the known role of SOX2 gene in the development and differentiation suggested that this transcription factor gene may be relevant to the aberrant growth of the glioma cells. A recent report suggested that the glial cells under these conditions are a better model of the human glioblastoma.[17] The term tumor-initiating cells are frequently described as cancer stem cell capacities.[18] According to the cancer stem cells fail to cure may be attributed to the current therapeutic strategies, which have been pointed at the tumor bulk without significant effect in cancer stem cell. Although the elimination of upregulated expression of SOX2 gene in cancer stem cell has been regarded as a prerequisite for the development of successful therapeutic strategies, it has not still been fully elucidated how their steaminess is maintained. To establish roles of the therapeutic strategy against glioma are faithfully recapitulated stem cell component. In this study, the author reviewed a comparative and functional analysis of the SOX family in mammals. In contrast, the SOX2 gene is necessary for the proliferation of human glioma cell and the downstream effect would be the ultimate target for glioblastoma therapy.


  Methods Top


Primary sequence and database

1. Primary sequence retrieved from the different specific database (UniProt, KEGG, EMBL, GenBank, and NCBI). 2. SMART web base application performed for identification of a specific domain in the query sequence. Pfam was searched for retrieving protein family information. SWISS-MODEL is a structural bioinformatics web server for comparative modeling of three-dimensional (3D) structure. It is the most accurate method for generating valid 3D structure and is routinely used in practical applications. This method makes the experimental protein structure to a build model for evolutionarily related proteins. The SWISS-MODEL is a continuously updated database of homology or comparative model of organism proteome for biomedical research. Genome: The genome sequences were downloaded from genomic data in different specialized databases (NCBI and Ensemble).

Stand-alone tools and gene ontology annotation

HMMER executed using multiple sequence alignments (MSAs) of the specific domain as a profile search. HMMER is a statistical algorithm, making MSA of the specific domain as a profile search, an implement methods using probabilistic models called the profile hidden Markov model. Stand-alone BLAST was performed for homolog gene in selected organisms. The BLAST2GO was performed for the gene ontology (GO) annotation. BLAST2GO is a bioinformatics and computational tool for high-throughput GO annotation of the specific sequence. The functional information retrieves via GO annotation a controlled vocabulary of the functional attribute.

Domain, motif, and phylogeny

MSA methods are used to calculate the best match of the homolog sequences and line them up so that the identity, similarity, and differences can be seen. MSA of the highest hit sequence analysis was carried out by a web-based tool called MultAlin for the identification of conserved domain. MEGA7 performed for constructing a phylogenetic tree using Neighbor-Joining Methods. The MEGA7 is a Bioinformatics tool for analysis of the molecular evolutionary relationship of the specific gene in various organisms. The MEME suite performed for the sequence motifs is a computational web-based tool for discovery and analysis of specific motifs.

Gene expression and chromosome location

The gene expression analysis was carried out using the GENEVESTIGATOR tool, which is a high-performance search engine of the gene expression in different biological contexts. GENEVESTIGATOR is used to identify and validate novel target. Chromosome location retrieves using gene card is a database of the human genes which provides genomic information of all known and predicted human genes. This database is currently available for biomedical information such as gene, encoded protein, and relevant disease.


  Results Top


Identification of the primary and secondary structures

The primary sequence demonstrated the specific composition of the nucleotide and peptide. The SOX2 gene composed 945 nucleotides and 317 peptides with 72 peptides binds to the DNA sequence, which is well known as an HMG domain [Figure 1] and [Supplementary Table 1]. The tertiary structure illustrated the HMG domain are involved in DNA binding and also involved in protein–protein interaction. The structure of the HMG-box domain consists of three helices in an irregular array. The HMG-box is a protein domain found in several mammalian genomes, which is involved in the regulation of DNA-dependent processes such as transcription, replication, and strand repair.
Figure 1: Tertiary structure (SOX2)

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Genome-wide identification and annotation

The genome-wide identification by HMMER algorithm results showed that the highest hits of 175 and 137 of HMG domains were found in Homo sapiens and Mus musculus, respectively [Supplementary Table 2]. The stand-alone BLAST results represent 101 and 84 of homologs in H. sapiens and M. musculus, respectively [Supplementary Table 2]. The multiple hits were selected from both organisms for GO annotation. The GO annotation demonstrated a total of 38 and 40 gene belong to the SOX family in Homo sapiens and Mus musculus respectively [Supplementary Table 3]. The GO level and annotation distribution in the H. sapiens demonstrated a total annotation of 2519, a mean level of 8.17, and a standard deviation of 3.147, whereas that in M. musculus, a total annotation of 2477, a mean level of 8.312, and a standard deviation of 3.092.{Table 2}{Table 3}



Identification of the domain, motifs, and phylogeny

The multiple hits of SOX2 gene listed from both organisms for sequence alignment. The MSA result demonstrated the conserved HMG domain. The high consensus (90%) indicates the extended HMG domain [Figure 2] and its specific motifs [Figure 3]. The phylogenetic tree demonstrated the molecular evolutionary relationship of the SOX2 gene in between H. sapiens and M. musculus. Particular clades represent the multifunctional genes involved in the SOX family [Figure 4].
Figure 2: Multiple sequence alignment (conserved high-mobility group domain)

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Figure 3: (a-c) Sequence motifs

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Figure 4: Phylogeny analysis (SOX family)

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Gene expression and chromosome location

Expression analysis of the SOX2 gene demonstrated nine anatomical neoplasia cell categories measure of one gene in H. sapiens was highly expressed in neoplasms of eye/brain/central nervous system, brain (encephalon), astrocytoma, glioblastoma, and oligodendroglioma [Figure 5]. The chromosome localization study demonstrated SOX2 gene located band 3q26.33 with start 204,073,115 bp and end 181,714,436 bp [Figure 6].
Figure 5: Gene expression (SOX2 gene)

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Figure 6: Chromosome location of SOX2 gene

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  Discussion Top


The aggressive surgery, radiotherapy, and chemotherapy treatments of malignant glioma remain powerful. Although the concept of molecular biology and cancer stem cells reveals a new framework of cancer therapeutic strategies against malignant glioma, it remains unclear how glioma cells could be eliminated. It is now widely accepted that the tumor at various stages of differentiation can perpetuate the tumor and analogy with their normal counterparts.[18],[19] The impossibility of identifying suitable markers in cells is defined as the smallest fraction of cancer cells in a malignancy that can propagate the tumor upon immunodeficient The impossibility of identifying suitable markers in cells is defined as the smallest fraction of cancer cells in a malignancy that can propagate the tumor upon immunodeficiency. In this study, the findings demonstrated that the SOX family is associated with the developmental process in mammals. In contrast, the SOX2 gene function maintains the proliferative potential of neural/precursor cells and ensures the production of sufficient cell number.[10],[12],[20] SOX2 expression is paralleled in the glioblastoma than the normal neural cells. The author then hypothesized that the SOX2 gene function is evolutionarily conserved in glioblastoma. The downregulation of SOX2 gene expression may be an earlier marker for the glioblastoma. The principle of transcription factor data analysis suggested that this approach may be the best choice to target glioblastoma cells. SOX2 gene expression in glioblastoma did not have a dramatic effect in the short term. Thus, no induction of massive apoptosis, cell senescence, and differentiation is involved in the regulation of the SOX2 gene expression. However, the SOX2 gene slowly and steadily decreases over time, which leads to its virtual disappearance. Those effects could be explained in the lengthening of the cell cycle. The overall study pointed out the exit of the SOX2 gene from the cell cycle. Indeed, the proportion of cells decreased and cells stopped proliferating right after SOX2 gene expression. In light of murine neural cells [9],[11] explain that the down-regulation of SOX2 gene expression indicates glioblastoma lose, a break that prevents differentiation. The glioblastoma cells progressively mature, if the exit from the cell cycle then eventually die and disappear during down-regulated expression of SOX2 gene. The proportion of the cells maturing is rather small especially heterogeneous inhabitants of glioblastoma which impaired and expressed differentiation marker. Although the direct evidence such as increase differentiation rate is difficult to obtain due to their impaired aberrant expression. Downregulated expression of SOX2 gene in neural cells usually high proportion of the cells not only exited from the cell cycle but increase the expression in neurons indicate that they become engaged in differentiation. The downregulated expression of SOX2 gene not only in precursor cells but in cancer cells shown the loss of tumorigenicity. It then appears that the SOX2 gene is fundamental for the maintenance of self-renewal capacity in the neural stem cells when they have cancer properties. The cells stop proliferating is the regardless mutations they have accumulated. Therefore, the down-regulated effect of SOX2 gene would be an ultimate target for glioblastoma therapy.

Acknowledgment

The author is grateful to Assam University, Silchar, Assam, India, for providing the requisite lab facilities in carrying out this research work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

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