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Differentially-expressed mRNAs, microRNAs and long noncoding RNAs in intervertebral disc degeneration identified by RNA-sequencing.

ABSTRACT: The underlying molecular mechanisms of intervertebral disc degeneration (IDD) remain unclear. This study aimed to identify the crucial molecules and explore the function of noncoding RNAs and related pathways in IDD. We randomly selected three samples each from an IDD and a spinal cord injury group (control) for RNA-sequencing. We identified 463 differentially-expressed long noncoding RNAs (lncRNAs), 47 differentially-expressed microRNAs (miRNAs), and 1,334 differentially-expressed mRNAs in IDD. Three hundred fifty-eight lncRNAs as cis-regulators could potentially target 865 genes. Protein-protein interaction (PPI) network analysis confirmed that IL-6, VEGFA, IGF1, MMP9, CXCL8, FGF2, IL1B, CCND1, ITGAM, PTPRC, FOS and PTGS2 were hub genes. We built a competing endogenous RNA (ceRNA) network and identified lncRNA XIST-hsa-miR-4775-PLA2G7 and lncRNA XIST-hsa-miR-424-5p-AMOT/TGFBR3 ceRNA axes. Quantitative real-time PCR (qRT-PCR) was implemented in 15 IDD samples and 15 controls to validate differentially-expressed genes in ceRNA axes. From the ceRNA network, gene ontology (GO) enrichment analysis indicated that noncoding RNAs were associated with several biological processes, including extracellular matrix organization, extracellular structure organization, leukocyte migration, and mesenchyme development. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that noncoding RNAs were associated with several pathways including the AGE-RAGE signaling pathway, PI3K-Akt signaling pathway, axon guidance, and osteoclast differentiation. These results indicate that some specific noncoding RNAs and ceRNA axes may be vital during the development of IDD, and may have potential as alternative diagnostic biomarkers as well as novel therapeutic strategies for IDD.

SUBMITTER: Li Z

PROVIDER: S-EPMC8806213 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:INTRODUCTION: In addition to the well-known short noncoding RNAs such as microRNAs (miRNAs), increasing evidence suggests that long noncoding RNAs (lncRNAs) act as key regulators in a wide aspect of biologic processes. Dysregulated expression of lncRNAs has been demonstrated being implicated in a variety of human diseases. However, little is known regarding the role of lncRNAs with regards to intervertebral disc degeneration (IDD). In the present study we aimed to determine whether lncRNAs are differentially expressed in IDD. METHODS: An lncRNA-mRNA microarray analysis of human nucleus pulposus (NP) was employed. Bioinformatics prediction was also applied to delineate the functional roles of the differentially expressed lncRNAs. Several lncRNAs and mRNAs were chosen for quantitative real-time PCR (qRT-PCR) validation. RESULTS: Microarray data profiling indicated that 116 lncRNAs (67 up and 49 down) and 260 mRNAs were highly differentially expressed with an absolute fold change greater than ten. Moreover, 1,052 lncRNAs and 1,314 mRNAs were differentially expressed in the same direction in at least four of the five degenerative samples with fold change greater than two. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for the differentially expressed mRNAs indicated a number of pathways, such as extracellular matrix (ECM)-receptor interaction. A coding-noncoding gene co-expression (CNC) network was constructed for the ten most significantly changed lncRNAs. Annotation terms of the coexpressed mRNAs were related to several known degenerative alterations, such as chondrocyte differentiation. Moreover, lncRNAs belonging to a particular subgroup were identified. Functional annotation for the corresponding nearby coding genes showed that these lncRNAs were mainly associated with cell migration and phosphorylation. Interestingly, we found that Fas-associated protein factor-1 (FAF1), which potentiates the Fas-mediated apoptosis and its nearby enhancer-like lncRNA RP11-296A18.3, were highly expressed in the degenerative discs. Subsequent qRT-PCR results confirmed the changes. CONCLUSIONS: This is the first study to demonstrate that aberrantly expressed lncRNAs play a role in the development of IDD. Our study noted that up-regulated RP11-296A18.3 highly likely induced the over-expression of FAF1, which eventually promoted the aberrant apoptosis of disc cells. Such findings further broaden the understanding of the etiology of IDD.

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Differentially-expressed mRNAs, microRNAs and long noncoding RNAs in intervertebral disc degeneration identified by RNA-sequencing.

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