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Differential microRNA expression patterns between TallyHo/JngJ mice and non-diabetic Swiss Webster Random/Jackson
David Carro Vázquez1, Lejla Emini2, Martina Rauner2
1TAmiRNA GmbH, Department of Research and Development, 1110 Vienna, Austria.
Abstract:
Type 2 diabetes mellitus (T2DM) increases the susceptibility of bone fragility. The underlying mechanisms have, however, remained largely unknown. MicroRNAs (miRNAs) are short single-stranded non-coding RNA molecules with utility as biomarkers due to their easy accessibility and stability in bodily fluids. Here, we aimed to use an unbiased approach to identify miRNAs dysregulated in a polygenic mouse model of T2DM. Genome-wide analysis of miRNAs in serum, BM, and bone from the polygenic TallyHo/JngJ (TH) mice, which recapitulate T2DM in humans, was performed. This analysis was compared to the recommended control Swiss Webster Random/Jackson (SWR/J) and a strain-matched non-diabetic control (TH-ND). When comparing TH mice with TH-ND using an adjusted p-value false discovery rate (FDR) cut-off of 0.2 to identify differentially expressed miRNAs, mmu-miR-466i-5p and mmu-miR-1195 were found to be up-regulated in both serum and in BM. Dysregulated miRNAs were not found in bone tissue. When comparing TH-ND mice with SWR/J using the same FDR cut-off, mmu-miR-351-5p, and mmu-miR-322-3p were upregulated in both BM and serum, while mmu-miR-449a-5p and mmu-miR-6240 were downregulated in BM and serum. Dysregulated miRNAs in BM or cortical bone compared to serum between TH-ND mice and SWR/J were investigated for their cell-type enrichment to identify putative donor cells and their gene target networks. Gene target network analysis revealed genes involved in diabetes-related signaling pathways as well as in diabetic bone disease. Cell-type enrichment analysis identified hsa-miR-449a enriched in immune cells, hsa-miR-592 in hepatocytes and endothelial cells, while hsa-miR-424-3p, hsa-miR-1-3p, and hsa-miR-196b-5p were enriched in mesenchymal stem cells and their derived tissues. In conclusion, our comparative miRNA profiling sheds light on differential expression patterns between SWR/J and both subgroups of TH. No differences were observed between TH and TH-ND, suggesting the genetic background of SWR/J may be responsible for the change of dysregulated miRNA.
Insights
MicroRNAs (miRNAs) are key biomarkers for type 2 diabetes mellitus (T2DM) and bone fragility. This study identified specific miRNAs dysregulated in T2DM mouse models, revealing potential links to diabetic bone disease.
Area of Science:
- Biochemistry
- Genetics
- Endocrinology
Background:
- Type 2 diabetes mellitus (T2DM) is linked to increased bone fragility, but the underlying mechanisms remain unclear.
- MicroRNAs (miRNAs) are stable biomarkers found in bodily fluids, offering potential for understanding disease mechanisms.
Purpose of the Study:
- To identify differentially expressed miRNAs in a polygenic mouse model of T2DM using an unbiased, genome-wide approach.
- To investigate the role of miRNAs in T2DM-associated bone fragility.
Main Methods:
- Genome-wide miRNA profiling was conducted on serum, bone marrow (BM), and bone tissue from TallyHo/JngJ (TH) mice (T2DM model), non-diabetic TH mice (TH-ND), and Swiss Webster Random/Jackson (SWR/J) controls.
- Differential expression analysis was performed using an adjusted p-value false discovery rate (FDR) cut-off of 0.2.
- Gene target network and cell-type enrichment analyses were utilized to identify potential cellular origins and functional pathways of dysregulated miRNAs.
Main Results:
- Up-regulation of mmu-miR-466i-5p and mmu-miR-1195 was observed in both serum and BM of TH mice compared to TH-ND mice.
- Comparing TH-ND mice to SWR/J mice revealed up-regulation of mmu-miR-351-5p and mmu-miR-322-3p, and down-regulation of mmu-miR-449a-5p and mmu-miR-6240 in both BM and serum.
- No significant miRNA dysregulation was found in bone tissue.
- Gene target analysis implicated miRNAs in diabetes-related signaling and diabetic bone disease.
- Cell-type enrichment identified miRNAs in immune cells, hepatocytes, endothelial cells, and mesenchymal stem cells.
Conclusions:
- Comparative miRNA profiling revealed distinct expression patterns between SWR/J and TH mouse groups.
- The observed miRNA dysregulation differences between TH-ND and SWR/J mice suggest the SWR/J genetic background may influence miRNA expression.
- These findings provide insights into potential miRNA involvement in T2DM-related bone fragility.
