Identification of a global gene expression signature associated with the genetic risk of catastrophic fracture in iPSC-derived osteoblasts from Thoroughbred horses
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1074832 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Bone fractures are a significant problem in Thoroughbred racehorses. The risk of fracture is influenced by both genetic and environmental factors. To determine the biological processes that affected in genetically susceptible horses, we utilised polygenic risk scoring to establish induced pluripotent stem cells (iPSCs) from horses at genetically high and low risk. RNA-sequencing on iPSC-derived osteoblasts revealed 112 genes that were significantly differentially expressed. 43 of these genes have known roles in bone, 27 are not yet annotated in the equine genome and 42 currently have no described role in bone. However, many of the proteins encoded by the known and unknown genes have reported interactions. Functional enrichment analyses revealed that the differentially expressed genes were overrepresented in progresses regulating the extracellular matrix and pathways known to be involved in bone remodelling and bone diseases. Gene set enrichment analysis also detected numerous biological processes and pathways involved in glycolysis that had a higher expression in the iPSC-osteoblasts from horses with low polygenic risk scores for fracture.Therefore, the differentially expressed genes may be relevant for maintaining bone homeostasis and contribute to fracture risk. A deeper understanding of the consequences of mis-regulation of these genes and the identification of the DNA variants which underpin their differential expression may reveal more about the molecular mechanisms which are involved in equine bone health and fracture risk.
2025-01-22 | GSE255417 | GEO
Project description:Stress fractures are microcracks in bone caused by repetitive loading and these microcracks can increase the risk of developing catastrophic fractures. Early detection of stress fractures can be difficult due to the necessity of accurate clinical detection. MicroRNAs could be used as potential diagnostic and prognostic biomarkers due to their size, abundance, tissue specificity and stability in body fluids. Global profiling of circulating plasma small RNA-sequencing between lame horses (stress fractures and non-stress fractures) and non-lame control horses and the effects and role of selected stress fracture-related miRNAs on equine bone marrow derived mesenchymal stem cells (BMMSCs) were investigated. The miRNA profiles of stress fracture cases and non-lame stress fracture cases were similar. No miRNA was identified for potential usage as a biomarker for differentiating stress fracture from lame cases. However, the miRNA profiles of lame cases and non-lame control horses were significantly different. RNA-sequencing showed three miRNAs (eca-miR-486-5p, eca-miR-26a and eca-miR-23a) were most significantly differentially expressed (p value <0.05) between lame cases and non-lame controls, which was validated by qPCR. Of these, eca-miR-486-5p demonstrated the most abundant and significant increased miRNA in the lame cases compared to non-lame control cases. Cell transfection experiments using the miR-486-5p mimic treatment in equine BMMSCs showed upregulation of the osteogenic transcription factor, Runt-related transcription factor 2 (RUNX2) and insulin-like growth factor type 1 (IGF1). A significant decrease of miR-133a in the miR-486-5p mimic treated cells was also demonstrated. Since RUNX2 is the known target of miR-133a, miR 486-5p together with miR-133a would suggest the biological importance of bone turnover and osteogenesis in equine BMMSCs, but further investigation of role of miR-486-5p and miR-133a in equine bone biology is warranted.
2024-05-23 | GSE268059 | GEO
Project description:Recurrent exertional rhabdomyolysis (RER) develops in 5-10% of Thoroughbred racehorses. High-stress environments, nervous temperament, and diet influence the presentation of RER. RER-susceptibility is associated with alterations in intramuscular Ca2+ regulation with detrimental effects on mitochondria. Our study aims to determine underlying molecular drivers influencing RER-susceptibility by comparing the muscle proteome of control, RER-susceptible, and RER horses treated with dantrolene. Animals used in this study were Thoroughbred mares in race training between episodes of RER.
2021-01-07 | PXD020100 | Pride
Project description:Whole genome sequencing of Thoroughbred horses
| PRJEB60529 | ENA
Project description:Osteoporosis and bone fragility fracture are multifactorial pathologies whose genetic component is still poorly characterized. The present experiment aims to identify genes differentially expressed in the bone-forming cell; the osteoblast. To do this, we obtain primary osteoblasts from bone explants of women undergoing hip replacement to later obtain RNA. The cases are women with a fragility bone fracture of the hip. The controls are women with severe osteoarthritis.Microarray analysis yielded 2542 differentially expressed transcripts belonging to 1798 annotated genes, of which 45.6% (819) were overexpressed, and 54.4% (979) underexpressed (fold-change between -7.45 and 4.0). Among the most represented pathways indicated by transcriptome analysis were chondrocyte development, positive regulation of bone mineralization, BMP signaling pathway, skeletal system development and Wnt signaling pathway. Then, we selected SNPs in genes related to epigenetic mechanisms to study their association with bone mass in a cohort of 1028 Spanish women. We used microarrays to compare the overall gene expression between primary osteoblasts from women with fragility fracture with that of control women undergoing hip replacement due to severe osteoatritis.
2020-10-01 | GSE156508 | GEO
Project description:Sixteen severly RAO (Recurrent Airway Obstruction) affected horses were studied. All RAO affected male horses were hybridized with GSM1332974 (Thoroughbred male 1, male reference), and the female horses were with GSM1332975 (Thoroughbred female 2, female reference). Finally results are compared with GSE55266 and two other control horses (SPA-H1-3 and SPA-H1-5) and relatively novel RAO CNVs were reported.
2016-03-07 | GSE63033 | GEO
Project description:Large scale transcriptional analysis of MHC haplotype diversity in UK thoroughbred Horses
| PRJEB57925 | ENA
Project description:Fractures caused by bone overloading are a leading cause of euthanasia in Thoroughbred racehorses. The risk of fatal fracture has been shown to be influenced by both environmental and genetic factors but, to date, no specific genetic mechanisms underpinning fractures have been identified. In this study, we utilised a genome-wide polygenic risk score to establish an in vitro cell system to study bone gene regulation in horses at high and low genetic risk of fracture. Candidate gene expression analysis revealed differential expression of COL3A1 and STAT1 genes in osteoblasts derived from high- and low-risk horses. Whole-genome sequencing of two fracture cases and two control horses revealed a single-nucleotide polymorphism (SNP) upstream of COL3A1 that was confirmed in a larger cohort to be significantly associated with fractures. Bioinformatics tools predicted that this SNP may impact the binding of the transcription factor SOX11. Gene modulation demonstrated SOX11 is upstream of COL3A1, and the region binds to nuclear proteins. Furthermore, luciferase assays demonstrated that the region containing the SNP has promoter activity. However, the specific effect of the SNP depends on the broader genetic background of the cells and suggests other factors may also be involved in regulating COL3A1 expression. In conclusion, we have identified a novel SNP that is significantly associated with fracture risk and provide new insights into the regulation of the COL3A1 gene.
| S-EPMC10778232 | biostudies-literature
Project description:We sequenced the whole mRNA of six thoroughbred horse (Equus caballus) blood and muscle tissues before and after exercising, generating a total of 1.3 billion short reads with 90-bp pair-end sequences from 24 samples. Comparing with current genome annotation, we identified 32,361 unigene clusters spanning 51.83 Mb that contained 11,933 (36.87%) annotated genes. More than 60% (20,428) unigene clusters did not match any current equine gene model. We identified 189,973 single nucleotide variations (SNVs) from the aligned sequences against the horse reference. Most SNVs (171,558 SNVs; 90.31%) were novel compared with over 1.1 million equine SNPs from two databases. Some genes have significantly different expression levels under different environment. We define those identical genes which have different expression levels are ‘differentially expressed’ and carried out differentially expressed gene analysis before and after exercise conditions. We discovered, 62 up- and 80 down-regulated genes in the blood and 878 up- and 285 down-regulated genes in the muscle from the 24 samples. Six out of 28 previously exercise-related known genes, HIF1A, ADRB2, PPARD, VEGF, TNC, and BDNF, were highly expressed in the muscle after exercise. We discovered 56 functionally unknown transcription factors that are probably associated with an early regulatory exercise mechanism from 91 differentially expressed transcription factors. We found interesting RNA expression patterns where different alternative splicing forms of the same gene showed reversed expressions before and after exercising. whole mRNA sequencing profiles of six thoroughbred horse (Equus caballus) blood and muscle tissues before and after exercising
2013-05-01 | E-GEOD-37870 | biostudies-arrayexpress
Project description:A single bout of exercise induces changes in gene expression in skeletal muscle. Regular exercise results in an adaptive response involving changes in muscle architecture and biochemistry, and is an effective way to manage and prevent common human diseases such as obesity, cardiovascular disorders and type II diabetes. Our study is a transcriptome-wide analysis of skeletal muscle tissue in a large cohort of untrained Thoroughbred horses before and after a bout of high-intensity exercise and again after an extended period of training. We hypothesized that regular high-intensity exercise training primes the transcriptome for the demands of high-intensity exercise.
2018-08-07 | E-MTAB-5447 | biostudies-arrayexpress