The miRNA-gene regulatory circuits in nSARS-CoV-2 and their potential correlations with pulmonary and thrombotic disorders

Abstract In view of the worldwide spread of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (nSARS-CoV-2) infection pandemic situation, research to repurpose drugs, identify novel drug targets, vaccine candidates, diagnostic markers etc have created a new race to curb the disease. To uncover nSARS-CoV-2-related important biological features and understanding the molecular basis of this disease, network biology and miRNA-gene regulatory motif-based approach is used. 11 antiviral human-microRNAs (miRNAs) which can potentially target SARS-CoV-2 genes were collated; their direct miRNA interactors were identified and a comprehensive nSARS-CoV-2 responsive miRNA:Transcription Factor (TF):gene coregulatory network was built. 1385 miRNA:TF:gene tripartite, Feed-Forward Loops (FFLs) were identified from the network. The network topology was mapped into the biological space and the overrepresented pathways were identified. Four regulatory circuits: hsa-mir-9-5p-EP300-PLCB4, hsa-mir-324-3p-MYC-HLA-F, hsa-mir-1827-E2F1-CTSV and hsa-mir-1277-5p-SP1-CANX are identified. These miRNA-gene regulatory circuits are found to regulate signalling pathways like virus endocytosis, viral replication, inflammatory response, pulmonary vascularization, cell cycle control, virus spike protein stabilization, antigen presentation, etc. Some novel computational evidences for understanding nSARS-CoV-2 molecular mechanisms controlled by these regulatory circuits is put forth. The novel associations of miRNAs and genes identified with this infection are open for experimental validation. Further, these regulatory circuits also suggest potential correlations/similarity in the molecular mechanisms during nSARS-CoV-2 infection and pulmonary diseases and thromboembolic disorders. A detailed molecular snapshot of TGF-β signalling pathway as the common mechanism that could play an important role in controlling common pathophysiology i.e. systemic inflammation, increased pulmonary pressure, ground glass opacities, D-dimer overexpression is also put forth.

Download Full-text

nSARS-Cov-2, pulmonary edema and thrombosis: possible molecular insights using miRNA-gene circuits in regulatory networks

ExRNA ◽

10.1186/s41544-020-00057-y ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

P. Khurana ◽

A. Gupta ◽

R. Sugadev ◽

Y. K. Sharma ◽

R. Varshney ◽

...

Keyword(s):

Pulmonary Edema ◽

Antigen Presentation ◽

Signaling Pathways ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Mirna Gene ◽

Protein Stabilization ◽

Molecular Signature ◽

Potential Candidate ◽

Regulatory Circuits

Abstract Background Given the worldwide spread of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (nSARS-CoV-2) infection pandemic situation, research to repurpose drugs, identify novel drug targets, vaccine candidates have created a new race to curb the disease. While the molecular signature of nSARS-CoV-2 is still under investigation, growing literature shows similarity among nSARS-CoV-2, pulmonary edema, and thromboembolic disorders due to common symptomatic features. A network medicine approach is used to to explore the molecular complexity of the disease and to uncover common molecular trajectories of edema and thrombosis with nSARS-CoV-2. Results and conclusion A comprehensive nSARS-CoV-2 responsive miRNA: Transcription Factor (TF): gene co-regulatory network was built using host-responsive miRNAs and it’s associated tripartite, Feed-Forward Loops (FFLs) regulatory circuits were identified. These regulatory circuits regulate signaling pathways like virus endocytosis, viral replication, inflammatory response, pulmonary vascularization, cell cycle control, virus spike protein stabilization, antigen presentation, etc. A unique miRNA-gene regulatory circuit containing a consortium of four hub FFL motifs is proposed to regulate the virus-endocytosis and antigen-presentation signaling pathways. These regulatory circuits also suggest potential correlations/similarity in the molecular mechanisms during nSARS-CoV-2 infection, pulmonary diseases and thromboembolic disorders and thus could pave way for repurposing of drugs. Some important miRNAs and genes have also been proposed as potential candidate markers. A detailed molecular snapshot of TGF signaling as the common pathway, that could play an important role in controlling common pathophysiologies among diseases, is also put forth.

Download Full-text

Identifying Alzheimer’s Disease-related miRNA Based on Semi-clustering

Current Gene Therapy ◽

10.2174/1566523219666190924113737 ◽

2019 ◽

Vol 19 (4) ◽

pp. 216-223 ◽

Cited By ~ 2

Author(s):

Tianyi Zhao ◽

Donghua Wang ◽

Yang Hu ◽

Ningyi Zhang ◽

Tianyi Zang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Targets ◽

Molecular Mechanisms ◽

Feature Vector ◽

Mirna Gene ◽

Interaction Network ◽

Gene Interaction ◽

Proteinprotein Interaction ◽

Synaptic Structures

Background: More and more scholars are trying to use it as a specific biomarker for Alzheimer’s Disease (AD) and mild cognitive impairment (MCI). Multiple studies have indicated that miRNAs are associated with poor axonal growth and loss of synaptic structures, both of which are early events in AD. The overall loss of miRNA may be associated with aging, increasing the incidence of AD, and may also be involved in the disease through some specific molecular mechanisms. Objective: Identifying Alzheimer’s disease-related miRNA can help us find new drug targets, early diagnosis. Materials and Methods: We used genes as a bridge to connect AD and miRNAs. Firstly, proteinprotein interaction network is used to find more AD-related genes by known AD-related genes. Then, each miRNA’s correlation with these genes is obtained by miRNA-gene interaction. Finally, each miRNA could get a feature vector representing its correlation with AD. Unlike other studies, we do not generate negative samples randomly with using classification method to identify AD-related miRNAs. Here we use a semi-clustering method ‘one-class SVM’. AD-related miRNAs are considered as outliers and our aim is to identify the miRNAs that are similar to known AD-related miRNAs (outliers). Results and Conclusion: We identified 257 novel AD-related miRNAs and compare our method with SVM which is applied by generating negative samples. The AUC of our method is much higher than SVM and we did case studies to prove that our results are reliable.

Download Full-text

Phenotypic plasticity can facilitate adaptive evolution in gene regulatory circuits

BMC Evolutionary Biology ◽

10.1186/1471-2148-11-5 ◽

2011 ◽

Vol 11 (1) ◽

Cited By ~ 64

Author(s):

Carlos Espinosa-Soto ◽

Olivier C Martin ◽

Andreas Wagner

Keyword(s):

Phenotypic Plasticity ◽

Adaptive Evolution ◽

Regulatory Circuits ◽

Gene Regulatory ◽

Gene Regulatory Circuits

Download Full-text

Construction of a Self-Consistent Landscape for Multistable Gene Regulatory Circuits

Biophysical Journal ◽

10.1016/j.bpj.2013.11.2146 ◽

2014 ◽

Vol 106 (2) ◽

pp. 379a

Author(s):

Mingyang Lu ◽

Jose Onuchic ◽

Eshel Ben-Jacob

Keyword(s):

Regulatory Circuits ◽

Self Consistent ◽

Gene Regulatory ◽

Gene Regulatory Circuits

Download Full-text

Integrated Gene Regulatory Circuits: Celebrating the 50th Anniversary of the Operon Model

Molecular Cell ◽

10.1016/j.molcel.2011.08.003 ◽

2011 ◽

Vol 43 (4) ◽

pp. 505-514 ◽

Cited By ~ 1

Author(s):

Shahragim Tajbakhsh ◽

Giacomo Cavalli ◽

Evelyne Richet

Keyword(s):

50Th Anniversary ◽

Regulatory Circuits ◽

Gene Regulatory ◽

Gene Regulatory Circuits

Download Full-text

Synthetic 5’ UTRs can either up- or down-regulate expression upon RBP binding

10.1101/174888 ◽

2017 ◽

Cited By ~ 1

Author(s):

Noa Katz ◽

Roni Cohen ◽

Oz Solomon ◽

Beate Kaufmann ◽

Orna Atar ◽

...

Keyword(s):

Regulatory Networks ◽

Cooperative Behavior ◽

Transcriptional Level ◽

Rna Molecules ◽

Regulatory Modules ◽

Regulatory Circuits ◽

Rna Hairpins ◽

Gene Regulatory ◽

Gene Regulatory Circuits

SUMMARYThe construction of complex gene regulatory networks requires both inhibitory and up-regulatory modules. However, the vast majority of RNA-based regulatory “parts” are inhibitory. Using a synthetic biology approach combined with SHAPE-Seq, we explored the regulatory effect of RBP-RNA interactions in bacterial 5’-UTRs. By positioning a library of RNA hairpins upstream of a reporter gene and co-expressing them with the matching RBP, we observed a set of regulatory responses, including translational stimulation, translational repression, and cooperative behavior. Our combined approach revealed three distinct states in-vivo: in the absence of RBPs, the RNA molecules can be found either in a molten state that is amenable to translation, or a structured phase that inhibits translation. In the presence of RBPs, the RNA molecules are in a semi-structured phase with partial translational capacity. Our work provides new insight into RBP-based regulation and a blueprint for designing complete gene regulatory circuits at the post-transcriptional level.

Download Full-text

Variation, Variegation and Heritable Gene Repression in S. cerevisiae

Frontiers in Genetics ◽

10.3389/fgene.2021.630506 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kholoud Shaban ◽

Safia Mahabub Sauty ◽

Krassimir Yankulov

Keyword(s):

Gene Expression ◽

Current Knowledge ◽

Regulatory Circuits ◽

Epigenetic Diversity ◽

Short And Long Term ◽

Unstructured Proteins ◽

Gene Regulatory ◽

Gene Regulatory Circuits ◽

Insight Into

Phenotypic heterogeneity provides growth advantages for a population upon changes of the environment. In S. cerevisiae, such heterogeneity has been observed as “on/off” states in the expression of individual genes in individual cells. These variations can persist for a limited or extended number of mitotic divisions. Such traits are known to be mediated by heritable chromatin structures, by the mitotic transmission of transcription factors involved in gene regulatory circuits or by the cytoplasmic partition of prions or other unstructured proteins. The significance of such epigenetic diversity is obvious, however, we have limited insight into the mechanisms that generate it. In this review, we summarize the current knowledge of epigenetically maintained heterogeneity of gene expression and point out similarities and converging points between different mechanisms. We discuss how the sharing of limiting repression or activation factors can contribute to cell-to-cell variations in gene expression and to the coordination between short- and long- term epigenetic strategies. Finally, we discuss the implications of such variations and strategies in adaptation and aging.

Download Full-text