Gene expression analysis reveals mir-29 as a linker regulatory molecule among rheumatoid arthritis, inflammatory bowel disease, and dementia: Insights from systems biology approach

Abstract

Background: Rheumatoid arthritis (RA) is a degenerative autoimmune disease, often managed through symptomatic treatment. The co-occurrence of the reported extra-articular comorbidities such as inflammatory bowel disease (IBD), and dementia may complicate the pathology of the disease as well as the treatment strategies. Therefore, in our study, we aim to elucidate the key genes, and regulatory elements implicated in the progression and association of these diseases, thereby highlighting the linked potential therapeutic targets.

Methodology: Ten microarray datasets each for RA, and IBD, and nine datasets for dementia were obtained from Gene Expression Omnibus. We identified common differentially expressed genes (DEGs) and constructed a gene-gene interaction network. Subsequently, topology analysis for hub gene identification, cluster and functional enrichment, and regulatory network analysis were performed. The hub genes were then validated using independent microarray datasets from Gene Expression Omnibus.

Results: A total of 198 common DEGs were identified from which CD44, FN1, IGF1, COL1A2, and POSTN were identified as the hub genes in our study. These hub genes were mostly enriched in significant processes and pathways like tissue development, collagen binding, cell adhesion, regulation of ERK1/2 cascade, PI3K-AKT signaling, and cell surface receptor signaling. Key transcription factors TWIST2, CEBPA, EP300, HDAC1, HDAC2, NFKB1, RELA, TWIST1, and YY1 along with the miRNA hsa-miR-29 were found to regulate the expression of the hub genes significantly. Among these regulatory molecules, miR-29 emerged as a significant linker molecule, bridging the molecular mechanisms of RA, IBD, and dementia. Validation of our hub genes demonstrated a similar expression trend in the independent datasets used for our study.

Conclusion: Our study underscores the significant role of miR-29 in modulating the expression of hub genes and the associated transcription factors, which are crucial in the comorbidity status of RA, dementia, and IBD. This regulatory mechanism highlights miR-29 as a key player in the pathogenesis of these comorbid diseases.

Fig 1. The schematic diagram representing the workflow of the study.

Fig 2

(a) The unique and shared DEGs across RA, IBD, and dementia. (b) Network of the common DEGs of RA, Dementia, and IBD. The nodes depict the genes and the edges represent the interaction between the nodes.

Fig 3. The topological analysis of the PPI network (a) Degree (b) Closeness (c) MCC.

Fig 4. Hub gene identification.

The unique and shared genes across the topological features degree, closeness, and MCC.

Fig 5. Gene cluster interaction network: The edges in lilac show co-expression, red edges show physical interactions, yellow edges depict shared protein domains and the blue edges code for pathways.

Fig 6. Immune cell expression.

Hub gene enrichment in the immune cells, where (a) CD44, and (b) IGF1 gene enrichment in the immune cells are shown.

Fig 7

(a) TF-hub gene network. The interaction network of the identified hub genes and the transcriptional factors. (b) Hub TF retrieval. Interaction network of the key transcription factors. The yellow nodes are the hub genes, green and red nodes are the key transcription factors.

Fig 8

a: The miRNA-hub gene interaction network, where the hub genes are denoted in yellow and the miRNAs are shown in blue nodes. b: Hub miRNA retrieval. The hub miRNAs predicted in our study through topological analysis using the (a) Betweenness, (b) Closeness, (c) Stress, and (d) Degree of the CytoHubba plugin of Cytoscape. The yellow color diamond nodes are the hub genes, the blue square nodes are the predicted miRNA, and the pink nodes are the predicted miRNAs that are common among all the four topology measures.

Fig 9. Expressional regulators and the target genes of miR-29 involved in the subprocesses associated with RA, IBD, and dementia.

Fig 10. Hub gene validation.

Expression level of hub genes in the validation datasets (a) GSE68689, (b) GSE9452, and (c) GSE140829.