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Investigation of MicroRNA and transcription factor mediated regulatory network for silicosis using systems biology approach.

ABSTRACT: Silicosis is a major health issue among workers exposed to crystalline silica. Genetic susceptibility has been implicated in silicosis. The present research demonstrates key regulatory targets and propagated network of gene/miRNA/transcription factor (TF) with interactions responsible for silicosis by integrating publicly available microarray data using a systems biology approach. Array quality is assessed with the Quality Metrics package of Bioconductor, limma package, and the network is constructed using Cytoscape. We observed and enlist 235 differentially expressed genes (DEGs) having up-regulation expression (85 nos) and down-regulation expression (150 nos.) in silicosis; and 24 TFs for the regulation of these DEGs entangled with thousands of miRNAs. Functional enrichment analysis of the DEGs enlighten that, the maximum number of DEGs are responsible for biological process viz, Rab proteins signal transduction (11 nos.) and Cellular Senescence (20 nos.), whereas IL-17 signaling pathway (16 nos.) and Signalling by Nuclear Receptors (14 nos.) etc. are Biological Pathway involving more DEGs. From the identified 1100 high target microRNA (miRNA)s involved in silicosis, 1055 miRNAs are found to relate with down-regulated genes and 847 miRNAs with up-regulated genes. The CDK19 gene (Up-regulated) is associated with 617 miRNAs whereas down-regulated gene ARID5B is regulated by as high as 747 high target miRNAs. In Prediction of Small-molecule signatures, maximum scoring small-molecule combinations for the DEGs have shown that CGP-60774 (with 20 combinations), alvocidib (with 15 combinations) and with AZD-7762 (24 combinations) with few other drugs having the high probability of success.

SUBMITTER: Choudhari JK

PROVIDER: S-EPMC7809153 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Investigation of MicroRNA and transcription factor mediated regulatory network for silicosis using systems biology approach.

Choudhari J K JK Verma M K MK Choubey J J Sahariah B P BP

Scientific reports 20210114 1

Silicosis is a major health issue among workers exposed to crystalline silica. Genetic susceptibility has been implicated in silicosis. The present research demonstrates key regulatory targets and propagated network of gene/miRNA/transcription factor (TF) with interactions responsible for silicosis by integrating publicly available microarray data using a systems biology approach. Array quality is assessed with the Quality Metrics package of Bioconductor, limma package, and the network is constr ...[more]

PMID: 33446673

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Project description:BACKGROUND:The elucidation of mammalian transcriptional regulatory networks holds great promise for both basic and translational research and remains one the greatest challenges to systems biology. Recent reverse engineering methods deduce regulatory interactions from large-scale mRNA expression profiles and cross-species conserved regulatory regions in DNA. Technical challenges faced by these methods include distinguishing between direct and indirect interactions, associating transcription regulators with predicted transcription factor binding sites (TFBSs), identifying non-linearly conserved binding sites across species, and providing realistic accuracy estimates. METHODOLOGY/PRINCIPAL FINDINGS:We address these challenges by closely integrating proven methods for regulatory network reverse engineering from mRNA expression data, linearly and non-linearly conserved regulatory region discovery, and TFBS evaluation and discovery. Using an extensive test set of high-likelihood interactions, which we collected in order to provide realistic prediction-accuracy estimates, we show that a careful integration of these methods leads to significant improvements in prediction accuracy. To verify our methods, we biochemically validated TFBS predictions made for both transcription factors (TFs) and co-factors; we validated binding site predictions made using a known E2F1 DNA-binding motif on E2F1 predicted promoter targets, known E2F1 and JUND motifs on JUND predicted promoter targets, and a de novo discovered motif for BCL6 on BCL6 predicted promoter targets. Finally, to demonstrate accuracy of prediction using an external dataset, we showed that sites matching predicted motifs for ZNF263 are significantly enriched in recent ZNF263 ChIP-seq data. CONCLUSIONS/SIGNIFICANCE:Using an integrative framework, we were able to address technical challenges faced by state of the art network reverse engineering methods, leading to significant improvement in direct-interaction detection and TFBS-discovery accuracy. We estimated the accuracy of our framework on a human B-cell specific test set, which may help guide future methodological development.

Project description:BackgroundMicroRNA (miRNA) is a class of small RNAs of ~22nt which play essential roles in many crucial biological processes and numerous human diseases at post-transcriptional level of gene expression. It has been revealed that miRNA genes tend to be clustered, and the miRNAs organized into one cluster are usually transcribed coordinately. This implies a coordinated regulation mode exerted by clustered miRNAs. However, how the clustered miRNAs coordinate their regulations on large scale gene expression is still unclear.ResultsWe constructed the miRNA-transcription factor regulatory network that contains the interactions between transcription factors (TFs), miRNAs and non-TF protein-coding genes, and made a genome-wide study on the regulatory coordination of clustered miRNAs. We found that there are two types of miRNA clusters, i.e. homo-clusters that contain miRNAs of the same family and hetero-clusters that contain miRNAs of various families. In general, the homo-clustered as well as the hetero-clustered miRNAs both exhibit coordinated regulation since the miRNAs belonging to one cluster tend to be involved in the same network module, which performs a relatively isolated biological function. However, the homo-clustered miRNAs show a direct regulatory coordination that is realized by one-step regulation (i.e. the direct regulation of the coordinated targets), whereas the hetero-clustered miRNAs show an indirect regulatory coordination that is realized by a regulation comprising at least three steps (e.g. the regulation on the coordinated targets by a miRNA through a sequential action of two TFs). The direct and indirect regulation target different categories of genes, the former predominantly regulating genes involved in emergent responses, the latter targeting genes that imply long-term effects.ConclusionThe genomic clustering of miRNAs is closely related to the coordinated regulation in the gene regulatory network. The pattern of regulatory coordination is dependent on the composition of the miRNA cluster. The homo-clustered miRNAs mainly coordinate their regulation rapidly, while the hetero-clustered miRNAs exert control with a delay. The diverse pattern of regulatory coordination suggests distinct roles of the homo-clustered and the hetero-clustered miRNAs in biological processes.

Project description:ObjectiveThe transcription factor networks that drive parotid salivary gland progenitor cells to terminally differentiate, remain largely unknown and are vital to understanding the regeneration process.MethodologyA systems biology approach was taken to measure mRNA and microRNA expression in vivo across acinar cell terminal differentiation in the rat parotid salivary gland. Laser capture microdissection (LCM) was used to specifically isolate acinar cell RNA at times spanning the month-long period of parotid differentiation.ResultsClustering of microarray measurements suggests that expression occurs in four stages. mRNA expression patterns suggest a novel role for Pparg which is transiently increased during mid postnatal differentiation in concert with several target gene mRNAs. 79 microRNAs are significantly differentially expressed across time. Profiles of statistically significant changes of mRNA expression, combined with reciprocal correlations of microRNAs and their target mRNAs, suggest a putative network involving Klf4, a differentiation inhibiting transcription factor, which decreases as several targeting microRNAs increase late in differentiation. The network suggests a molecular switch (involving Prdm1, Sox11, Pax5, miR-200a, and miR-30a) progressively decreases repression of Xbp1 gene transcription, in concert with decreased translational repression by miR-214. The transcription factor Xbp1 mRNA is initially low, increases progressively, and may be maintained by a positive feedback loop with Atf6. Transfection studies show that Xbp1 activates the Mist1 promoter [corrected]. In addition, Xbp1 and Mist1 each activate the parotid secretory protein (Psp) gene, which encodes an abundant salivary protein, and is a marker of terminal differentiation.ConclusionThis study identifies novel expression patterns of Pparg, Klf4, and Sox11 during parotid acinar cell differentiation, as well as numerous differentially expressed microRNAs. Network analysis identifies a novel stemness arm, a genetic switch involving transcription factors and microRNAs, and transition to an Xbp1 driven differentiation network. This proposed network suggests key regulatory interactions in parotid gland terminal differentiation.

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Investigation of MicroRNA and transcription factor mediated regulatory network for silicosis using systems biology approach.

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Investigation of MicroRNA and transcription factor mediated regulatory network for silicosis using systems biology approach.

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