Network Analysis Identifies Gene Regulatory Network Indicating the Role of RUNX1 in Human Intervertebral Disc Degeneration

Khan, Nazir M.; Díaz-Hernández, Martha Elena; Presciutti, Steven M.; Drissi, Hicham

doi:10.3390/genes11070771

Cited by 10 publications

(14 citation statements)

References 39 publications

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“…Genes identified in the network-cluster 1 for each NP and AF cells were subjected to transcription factor (TF)-target gene regulatory network analysis to identify the candidate transcription factors as described previously 77 , 78 . We performed iRegulon (version 1.3) analysis using Cytoscape 34 to examine the transcription factor binding motifs enriched in the genomic regions of our query gene set.…”

Section: Methodsmentioning

confidence: 99%

Single-cell RNA-seq identifies unique transcriptional landscapes of human nucleus pulposus and annulus fibrosus cells

Fernandes

Khan

Trochez

et al. 2020

Sci Rep

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Intervertebral disc (IVD) disease (IDD) is a complex, multifactorial disease. While various aspects of IDD progression have been reported, the underlying molecular pathways and transcriptional networks that govern the maintenance of healthy nucleus pulposus (NP) and annulus fibrosus (AF) have not been fully elucidated. We defined the transcriptome map of healthy human IVD by performing single-cell RNA-sequencing (scRNA-seq) in primary AF and NP cells isolated from non-degenerated lumbar disc. Our systematic and comprehensive analyses revealed distinct genetic architecture of human NP and AF compartments and identified 2,196 differentially expressed genes. Gene enrichment analysis showed that SFRP1, BIRC5, CYTL1, ESM1 and CCNB2 genes were highly expressed in the AF cells; whereas, COL2A1, DSC3, COL9A3, COL11A1, and ANGPTL7 were mostly expressed in the NP cells. Further, functional annotation clustering analysis revealed the enrichment of receptor signaling pathways genes in AF cells, while NP cells showed high expression of genes related to the protein synthesis machinery. Subsequent interaction network analysis revealed a structured network of extracellular matrix genes in NP compartments. Our regulatory network analysis identified FOXM1 and KDM4E as signature transcription factor of AF and NP respectively, which might be involved in the regulation of core genes of AF and NP transcriptome.

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Section: Methodsmentioning

confidence: 99%

Single-cell RNA-seq identifies unique transcriptional landscapes of human nucleus pulposus and annulus fibrosus cells

Fernandes

Khan

Trochez

et al. 2020

Sci Rep

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“…Based on the previous achievements and confidence [ 22 , 23 ], Runx1 indeed plays a cardinal role in leveraging the chondrogenic pathway to alter the BMSCs’ differentiation commitment [ 24 ], regulates the expression of Type II collagen [ 25 ], and controls the MSCs’ proliferation and survival [ 26 , 27 ]. Nevertheless, the role of Runx1 in the progression and pathogenesis of disc degeneration is controversial, with limited information available [ 34 , 35 ]. Interestingly, Runx2 has been demonstrated to regulate osteoblast differentiation and chondrocyte hypertrophy, but Runx1 suppresses Runx2 expression [ 24 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Runx1 Messenger RNA Delivered by Polyplex Nanomicelles Alleviate Spinal Disc Hydration Loss in a Rat Disc Degeneration Model

Chang

Tsou

Chang

et al. 2022

IJMS

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Vertebral disc degenerative disease (DDD) affects millions of people worldwide and is a critical factor leading to low back and neck pain and consequent disability. Currently, no strategy has addressed curing DDD from fundamental aspects, because the pathological mechanism leading to DDD is still controversial. One possible mechanism points to the homeostatic status of extracellular matrix (ECM) anabolism, and catabolism in the disc may play a vital role in the disease’s progression. If the damaged disc receives an abundant amount of cartilage, anabolic factors may stimulate the residual cells in the damaged disc to secrete the ECM and mitigate the degeneration process. To examine this hypothesis, a cartilage anabolic factor, Runx1, was expressed by mRNA through a sophisticated polyamine-based PEG-polyplex nanomicelle delivery system in the damaged disc in a rat model. The mRNA medicine and polyamine carrier have favorable safety characteristics and biocompatibility for regenerative medicine. The endocytosis of mRNA-loaded polyplex nanomicelles in vitro, mRNA delivery efficacy, hydration content, disc shrinkage, and ECM in the disc in vivo were also examined. The data revealed that the mRNA-loaded polyplex nanomicelle was promptly engulfed by cellular late endosome, then spread into the cytosol homogeneously at a rate of less than 20 min post-administration of the mRNA medicine. The mRNA expression persisted for at least 6-days post-injection in vivo. Furthermore, the Runx1 mRNA delivered by polyplex nanomicelles increased hydration content by ≈43% in the punctured disc at 4-weeks post-injection (wpi) compared with naked Runx1 mRNA administration. Meanwhile, the disc space and ECM production were also significantly ameliorated in the polyplex nanomicelle group. This study demonstrated that anabolic factor administration by polyplex nanomicelle-protected mRNA medicine, such as Runx1, plays a key role in alleviating the progress of DDD, which is an imbalance scenario of disc metabolism. This platform could be further developed as a promising strategy applied to regenerative medicine.

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“…Network-based approaches have recently appeared to be a powerful tool to investigate pathobiological processes and the molecular complexity of disease aetiology by identifying disease-specific network clusters such as MCODE clusters in PPI networks. The nodes participating in these particular regions usually have critical roles and biological functions 52 . Nodes participating in regulatory motifs also are of biological importance in GRNs 53 .…”

Section: Discussionmentioning

confidence: 99%

A Motif-Based Network Analysis of Regulatory Patterns in Doxorubicin Effects on Treating Breast Cancer, a Systems Biology Study

Dehghan¹,

Mirmotalebisohi²,

Sameni³

et al. 2022

AJMB

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Background: Breast cancer is the most common malignancy worldwide. Doxorubicin is an anthracycline used to treat breast cancer as the first treatment choice. Nevertheless, the molecular mechanisms underlying the response to Doxorubicin and its side effects are not comprehensively understood so far. We used systems biology and bioinformatics methods to identify essential genes and molecular mechanisms behind the body response to Doxorubicin and its side effects in breast cancer patients. Methods: Omics data were extracted and analyzed to construct the protein-protein interaction and gene regulatory networks. Network analysis was performed to identify hubs, bottlenecks, clusters, and regulatory motifs to evaluate crucial genes and molecular mechanisms behind the body response to Doxorubicin and its side effects. Results: Analyzing the constructed PPI and gene-TF-miRNA regulatory network showed that MCM3, MCM10, and TP53 are key hub-bottlenecks and seed proteins. Enrichment analysis also revealed cell cycle, TP53 signaling, Forkhead box O (FoxO) signaling, and viral carcinogenesis as essential pathways in response to this drug. Besides, SNARE interactions in vesicular transport and neurotrophin signaling were identified as pathways related to the side effects of Doxorubicin. The apoptosis induction, DNA repair, invasion inhibition, metastasis, and DNA replication are suggested as critical molecular mechanisms underlying Doxorubicin anti-cancer effect. SNARE interactions in vesicular transport and neurotrophin signaling and FoxO signaling pathways in glucose metabolism are probably the mechanisms responsible for side effects of Doxorubicin. Conclusion: Following our model validation using the existing experimental data, we recommend our other newly predicted biomarkers and pathways as possible molecular mechanisms and side effects underlying the response to Doxorubicin in breast cancer requiring further investigations.

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Network Analysis Identifies Gene Regulatory Network Indicating the Role of RUNX1 in Human Intervertebral Disc Degeneration

Cited by 10 publications

References 39 publications

Single-cell RNA-seq identifies unique transcriptional landscapes of human nucleus pulposus and annulus fibrosus cells

Single-cell RNA-seq identifies unique transcriptional landscapes of human nucleus pulposus and annulus fibrosus cells

Runx1 Messenger RNA Delivered by Polyplex Nanomicelles Alleviate Spinal Disc Hydration Loss in a Rat Disc Degeneration Model

A Motif-Based Network Analysis of Regulatory Patterns in Doxorubicin Effects on Treating Breast Cancer, a Systems Biology Study

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