Single-nucleotide-polymorphism-adjacent super enhancer network mediates enhanced osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE153312 | GEO | 2021/02/21
REPOSITORIES: GEO
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Project description:In order to recapitulated the primary mechanism of the pathologically enhanced osteogenesis of mesenchymal stem cells from ankylosing spondylitis patients (ASMSCs) over MSCs from healthy donor, we performed multiomic high-throughput sequencing. We analysed the H3K27ac ChIP-seq data according to ROSE algorithm, and identified super enhancers (SEs) in ASMSCs and HDMSCs. The ASMSC-unique SEs (ASUSEs) are associated with osteogenic differentiation and AS pathogenesis. By integrated analysis of H3K27ac ChIP-seq, ankylosing spondylitis (AS) SNPs and RNA-seq data, we discovered the transcription network regulated by AS SNP-adjacent super enhancers (SASEs) during the enhanced osteogenic differentiation of MSCs from AS patients (ASMSCs), which helped us gain insight into the crutial mechanism of AS pathological osteogenesis. And based on the inhibition effect of SE inhibitor JQ1 on the enhanced osteogenic differentiation of ASMSCs, we proposed that SEs may be attractive targets to treat AS pathological osteogenesis.
2021-02-21 | GSE153311 | GEO
Project description:In order to recapitulated the primary mechanism of the pathologically enhanced osteogenesis of mesenchymal stem cells from ankylosing spondylitis patients (ASMSCs) over MSCs from healthy donor, we performed multiomic high-throughput sequencing. We analysed the H3K27ac ChIP-seq data according to ROSE algorithm, and identified super enhancers (SEs) in ASMSCs and HDMSCs. The ASMSC-unique SEs (ASUSEs) are associated with osteogenic differentiation and AS pathogenesis. By integrated analysis of H3K27ac ChIP-seq, ankylosing spondylitis (AS) SNPs and RNA-seq data, we discovered the transcription network regulated by AS SNP-adjacent super enhancers (SASEs) during the enhanced osteogenic differentiation of MSCs from AS patients (ASMSCs), which helped us gain insight into the crutial mechanism of AS pathological osteogenesis. And based on the inhibition effect of SE inhibitor JQ1 on the enhanced osteogenic differentiation of ASMSCs, we proposed that SEs may be attractive targets to treat AS pathological osteogenesis.
2021-02-21 | GSE153310 | GEO
Project description:Single-nucleotide-polymorphism-adjacent super enhancer network mediates enhanced osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis.
| PRJNA642133 | ENA
Project description:Single-nucleotide-polymorphism-adjacent super enhancer network mediates enhanced osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis [RNA-seq]
| PRJNA642241 | ENA
Project description:Single-nucleotide-polymorphism-adjacent super enhancer network mediates enhanced osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis [ChIP-seq]
| PRJNA642242 | ENA
Project description:The aim of this study was to identify new genetic variants associated with the severity of ankylosing spondylitis (AS). We sequenced the exome of eight patients diagnosed with AS, selected on the basis of the severity of their clinical parameters. We identified 27 variants in exons and regulatory regions. The contribution of candidate variants found to AS severity was validated by genotyping two Spanish cohorts consisting of 180 cases/300 controls and 419 cases/656 controls. Relationships of SNPs and clinical variables with the Bath Ankylosing Spondylitis Disease Activity and Functional Indices BASDAI and BASFI were analyzed. BASFI was standardized by adjusting for the duration of the disease since the appearance of the first symptoms. Refining the analysis of SNPs in the two cohorts, we found that the rs4819554 minor allele G in the promoter of the IL17RA gene was associated with AS (p<0.005). This variant was also associated with the BASFI score. Classifying AS patients by the severity of their functional status with respect to BASFI/disease duration of the 60th, 65th, 70th and 75th percentiles, we found the association increased from p60 to p75 (cohort 1: p<0.05 to p<0.01; cohort 2: p<0.01 to p<0.005). Our findings indicate a genetic role for the IL17/ILRA axis in the development of severe forms of AS.
| S-EPMC4945092 | biostudies-literature
Project description:The mechanism of pathological osteogenesis in Ankylosing spondylitis (AS) is largely unknown. Our previous studies demonstrated that the imbalance between BMP-2 and Noggin secretion induces abnormal osteogenic differentiation of marrow-derived mesenchymal stem cells (MSCs) from AS patients in a two-dimensional culture environment. In this study, HA/β-TCP scaffolds were further used as a three-dimensional (3D) biomimetic culture system to mimic the bone microenvironment in vivo to determine the abnormal osteogenic differentiation of AS-MSCs. We demonstrated that when cultured in HA/β-TCP scaffolds, AS-MSCs had a stronger osteogenic differentiation capacity than that of MSCs from healthy donors (HD-MSCs) in vitro and in vivo. This dysfunction resulted from BMP2 overexpression in AS-MSCs, which excessively activated the Smad1/5/8 and ERK signalling pathways and finally led to enhanced osteogenic differentiation. Both the signalling pathway inhibitors and siRNAs inhibiting BMP2 expression could rectify the enhanced osteogenic differentiation of AS-MSCs. Furthermore, BMP2 expression in ossifying entheses was significantly higher in AS patients. In summary, our study demonstrated that AS-MSCs possess enhanced osteogenic differentiation in HA/β-TCP scaffolds as a 3D biomimetic microenvironment because of BMP2 overexpression, but not Noggin. These results provide insights into the mechanism of pathological osteogenesis, which can aid in the development of niche-targeting medications for AS.
| S-EPMC6484086 | biostudies-literature
Project description:The aim of this study was to explore the correlation of salazosulfamide efficacy on ankylosing spondylitis and N-acetyltransferase 1 (NAT1) gene polymorphism. Thirty-two patients with ankylosing spondylitis were recruited in the experimental group and 36 normal individuals were recruited to the control group. The experimental group received 8.0 mg of salazosulfamide (MTX) per week and the control group received isodose of normal saline. Twenty-six patients in the experimental group responded to the salazosulfamide treatment and 6 did not show response. Morning stiffness time of patients in the experimental group who responded to salazosulfamide was significantly lower than that of patients with no reaction to salazosulfamide, and similar to patients in the control group. The average tender joint count of patients in the experimental group that responded to salazosulfamide was lower than in patients with no response to treatment, and similar to patients in the control group. NAT1 gene sequencing determined that the patients sensitive to salazosulfamide treatment manifested as AA/AG at 263 locus, whereas patients not sensitive to salazosulfamide were GG. NAT1 expression was comparable between the different genotypes at the mRNA level. However, there was a significant difference of NAT1 protein between groups. Overall, salazosulfamide demonstrates curative activity for ankylosing spondylitis and we believe that NAT1 AA/GG genotype at 263 locus can promote salazosulfamide effectiveness on ankylosing spondylitis.
| S-EPMC5585730 | biostudies-other
Project description:Objectives:To explore the functions of RUNX3 single nucleotide polymorphisms (SNPs) associated with ankylosing spondylitis (AS). Methods:Individual SNP associations were evaluated in 4230 UK cases. Their effects on transcription factor (TF) binding, transcription regulation, chromatin modifications, gene expression and gene interactions were tested by database interrogation, luciferase reporter assays, electrophoretic mobility gel shifts, chromatin immunoprecipitation and real-time PCR. Results:We confirmed the independent association of AS with rs4265380, which was robust (P=4.7×10-6) to conditioning on another nearby AS-associated RUNX3 SNP (rs4648889). A RUNX3 haplotype incorporating both SNPs was strongly associated with AS (OR 6.2; 95%?CI 3.1 to 13.2, P=1.4×10-8). In a large UK cohort, rs4265380 is associated with leucocyte counts (including monocytes). RUNX3 expression is lower in AS peripheral blood mononuclear cells than healthy controls (P<0.002), independent of rs4265380 genotype. Enhancer function for this RUNX3 region was suggested by increased luciferase activity (approximately tenfold; P=0.005) for reporter constructs containing rs4265380. In monocytes, there was differential allelic binding of nuclear protein extracts to a 50?bp DNA probe containing rs4265380 that was strongly augmented by lipopolysaccharide activation. TF binding also included the histone modifier p300. There was enrichment for histone modifications associated with active enhancer elements (H3K27Ac and H3K79Me2) that may be allele dependent. Hi-C database interrogation showed chromosome interactions of RUNX3 bait with the nearby RP4-799D16.1 lincRNA. Conclusions:The association of AS with this RUNX3 regulatory region involves at least two SNPs apparently operating in different cell types. Monocytes may be potential therapeutic targets in AS.
| S-EPMC5845418 | biostudies-literature
Project description:INTRODUCTION: Ankylosing spondylitis (AS) is a severe, chronic inflammatory disease strongly associated with HLA-B27. The presence of additional HLA risk factors has been suggested by several studies. The aim of the current study is to assess the occurrence of an additional HLA susceptibility locus in the region between HLA-E and HLA-C in the Sardinian population. METHODS: 200 random controls, 120 patients with AS and 175 HLA-B27 positive controls were genotyped for six single nucleotide polymorphisms (SNPs) spanning the HLA region between HLA-E and HLA-C loci previously shown to harbour an additional susceptibility locus for AS. Allele, genotype and haplotype frequencies were compared. RESULTS: The data confirm our previous finding of a significant increase in patients with AS of allele A at SNP rs1264457 encoding for an Arg at the functional HLA-E polymorphism (Arg128/Gly128). This was due to a remarkable increase in the frequency of genotype A/A in patients vs HLA-B27-matched controls (51% vs 29%; P for trend: 5 x 10-5). Genotype distribution of three other SNPs mapping in genes (GNL1, PRR3 and ABCF-1) close to HLA-E and showing high LD with it, was also significantly skewed. Accordingly, haplotype distribution was also remarkably different. The frequency of the haplotype AAGA, is 42% in random controls, increases to 53% in the HLA-B27-positive controls, and reaches 68% in patients with AS (P values: 2 x 10-11 vs random and 3 x 10-4 vs HLA-B27 controls). CONCLUSIONS: There is a strong association between the presence of a haplotype in genes mapping between HLA-E and HLA-C and AS due to an increase of homozygous markers in patients. The strongest association however, is with the HLA-E functional polymorphism rs1264457. Since HLA-E is the ligand for the NKG2A receptor, these data point to the natural killer (NK) activity as possible player in the pathogenesis of AS.
| S-EPMC3003531 | biostudies-literature