RNA-sequencing analysis of hand cartilage tissue from osteoarthritis patients with/without common polymorphic variants in ALDH1A2 gene
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE216832 | GEO | 2023/01/01
REPOSITORIES: GEO
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Project description:RNA-sequencing analysis of hand cartilage tissue from osteoarthritis patients with/without common polymorphic variants in ALDH1A2 gene
| PRJNA895460 | ENA
Project description:Genome-wide association studies (GWAS) have identified over 100 loci associated with OA risk, but the majority of OA risk variants are non-coding, making it difficult to identify the impacted genes for further study and therapeutic development. To address this need, we used a multi-omic approach and genome editing to identify and functionally characterize putative OA risk genes. Computational analysis of GWAS and ChIP-seq data revealed that chondrocyte regulatory loci are enriched for OA risk variants. Mapping active enhancers in primary human chondrocytes and intersecting them with OA GWAS variants produced a refined list of putative causal variants. Identifying DNA loops in the chondrocyte cell line C28/I2 using in situ Hi-C allowed us to connect those putative causal variants to target genes and revealed SOCS2 as a putative mediator of OA risk. CRISPR-Cas9-mediated deletion of SOCS2 in primary human chondrocytes from three independent donors led to heightened expression of inflammatory markers in response to a cartilage matrix breakdown product of fibronectin. In total, we identified 56 putative OA risk genes—including 20 that are connected to OA risk SNPs via DNA looping—for further research and potential therapeutic development.
2022-09-07 | GSE200345 | GEO
Project description:Milky spots, lymphoid clusters present in visceral adipose tissue omentum, play central roles in the regulation of abdominal immunity. Milky spots exhibit hybrid nature between secondary lymph organs and ectopic lymphoid tissues, yet the mechanism of their development and maturation is poorly understood. Here, we identified a subset of fibroblastic reticular cells (FRCs) that are uniquely present in omental milky spots. These FRCs were characterized by the expression of retinoic acid converting enzyme, Aldh1a2, and endothelial cell marker, Tie2, in addition to canonical FRC-associated genes. Diphtheria toxin-mediated ablation of Aldh1a2+ FRCs resulted in the alteration in milky spot structure with a significant reduction in size and cellularity. Mechanistically, Aldh1a2+ FRCs regulated the display of chemokine CXCL12 on high endothelial venules (HEVs), which recruit blood-borne lymphocytes from circulation. We further found that Aldh1a2+ FRCs are required for the maintenance of peritoneal lymphocyte composition. These results illustrate the homeostatic roles of FRCs in the formation of non-classical lymphoid tissues.
2023-02-14 | GSE224023 | GEO
Project description:Milky spots, lymphoid clusters present in visceral adipose tissue omentum, play central roles in the regulation of abdominal immunity. Milky spots exhibit hybrid nature between secondary lymph organs and ectopic lymphoid tissues, yet the mechanism of their development and maturation is poorly understood. Here, we identified a subset of fibroblastic reticular cells (FRCs) that are uniquely present in omental milky spots. These FRCs were characterized by the expression of retinoic acid converting enzyme, Aldh1a2, and endothelial cell marker, Tie2, in addition to canonical FRC-associated genes. Diphtheria toxin-mediated ablation of Aldh1a2+ FRCs resulted in the alteration in milky spot structure with a significant reduction in size and cellularity. Mechanistically, Aldh1a2+ FRCs regulated the display of chemokine CXCL12 on high endothelial venules (HEVs), which recruit blood-borne lymphocytes from circulation. We further found that Aldh1a2+ FRCs are required for the maintenance of peritoneal lymphocyte composition. These results illustrate the homeostatic roles of FRCs in the formation of non-classical lymphoid tissues.
2023-02-14 | GSE224483 | GEO
Project description:Milky spots, lymphoid clusters present in visceral adipose tissue omentum, play central roles in the regulation of abdominal immunity. Milky spots exhibit hybrid nature between secondary lymph organs and ectopic lymphoid tissues, yet the mechanism of their development and maturation is poorly understood. Here, we identified a subset of fibroblastic reticular cells (FRCs) that are uniquely present in omental milky spots. These FRCs were characterized by the expression of retinoic acid converting enzyme, Aldh1a2, and endothelial cell marker, Tie2, in addition to canonical FRC-associated genes. Diphtheria toxin-mediated ablation of Aldh1a2+ FRCs resulted in the alteration in milky spot structure with a significant reduction in size and cellularity. Mechanistically, Aldh1a2+ FRCs regulated the display of chemokine CXCL12 on high endothelial venules (HEVs), which recruit blood-borne lymphocytes from circulation. We further found that Aldh1a2+ FRCs are required for the maintenance of peritoneal lymphocyte composition. These results illustrate the homeostatic roles of FRCs in the formation of non-classical lymphoid tissues.
2023-02-14 | GSE224315 | GEO
Project description:Histidine-rich glycoprotein (HRG) HRG is a liver-produced protein circulating in human plasma serum at high concentrations of around 125 ug/mL. HRG belongs to the family of type-3 cystatins and has been implicated in a plethora of biological processes, albeit its precise function is still not well understood. Human HRG is a highly polymorphic protein, with at least 5 variants with minor allele frequencies (MAF) of more than 10%, variable in populations from different parts of the world. Considering these 5 mutations we can expect already 35 = 243 possible possibly genetic HRG variants in the population. Here, we purified HRG from serum of 44 individual donors and investigated by proteomics the occurrence of different allotypes, each being either homozygote or heterozygote for each of the 5 mutation sites. We observed that some mutational combinations in HRG were highly favored, while others were apparently missing, although they ought to be present based on the stochastic independent assembly of these 5 mutation sites. To further explore this behavior, we extracted data from the 1000 genome project (n ~ 2500 genomes) and assessed the frequency of different HRG mutants in this larger dataset, observing a prevailing agreement with our proteomics data. From all the proteogenomic data we conclude that the 5 different (frequent) mutations sites in HRG are not occurring independently, but some mutational variants at different sites are fully mutually exclusive, whereas other are highly intwined. Specific mutations also affect HRG abundance and its glycosylation. As the levels of HRG have been suggested as a protein biomarker in a variety of biological processes (e.g., aging, COVID-19 severity, severity of bacterial infections), we here conclude that the highly polymorphic nature of the protein needs to be considered in such evaluations, as these mutations affect HRG’s abundance, structure, post-translational modifications, and function.
2023-10-24 | PXD040914 | Pride
Project description:RNA-seq analysis was performed in a T-cell acute lymphoblastic leukemia cell line (Jurkat) to analyze gene expression changes after ALDH1A2 depletion.
2020-12-31 | GSE136416 | GEO
Project description:Epitope mapping studies aim to identify the binding sites of antibody-antigen interactions to enhance the development of vaccines, diagnostics and immunotherapeutic compounds. However, mapping is a laborious process employing time- and resource-consuming ‘wet bench’ techniques or epitope prediction software that are still in their infancy. For polymorphic antigens, another challenge is characterizing cross-reactivity between epitopes, teasing out distinctions between broadly cross-reactive responses, limited cross-reactions among variants and the truly type-specific responses. A refined understanding of cross-reactive antibody binding could guide the selection of the most informative subsets of variants for diagnostics and multivalent subunit vaccines. We explored the antibody binding reactivity of sera from human patients and Peromyscus leucopus rodents infected with Borrelia burgdorferi to the polymorphic outer surface protein C (OspC), an attractive candidate antigen for vaccine and improved diagnostics for Lyme disease. We constructed a protein microarray displaying 23 natural variants of OspC and quantified the degree of cross-reactive antibody binding between all pairs of variants, using Pearson correlation calculated on the reactivity values using three independent transforms of the raw data: (1) logarithmic, (2) rank, and (3) binary indicators. We observed that the global amino acid sequence identity between OspC pairs was a poor predictor of cross-reactive antibody binding. Then we asked if specific regions of the protein would better explain the observed cross-reactive binding and performed in silico screening of the linear sequence and 3-dimensional structure of OspC. This analysis pointed to the C-terminal helix of the structure as a major determinant of type-specific cross-reactive antibody binding. We developed bioinformatics methods to systematically analyze the relationship between local sequence/structure variation and cross-reactive antibody binding patterns among variants of a polymorphic antigen, and this method can be applied to other polymorphic antigens for which immune response data is available for multiple variants.
2013-04-12 | GSE45996 | GEO
Project description:Epitope mapping studies aim to identify the binding sites of antibody-antigen interactions to enhance the development of vaccines, diagnostics and immunotherapeutic compounds. However, mapping is a laborious process employing time- and resource-consuming M-bM-^@M-^Xwet benchM-bM-^@M-^Y techniques or epitope prediction software that are still in their infancy. For polymorphic antigens, another challenge is characterizing cross-reactivity between epitopes, teasing out distinctions between broadly cross-reactive responses, limited cross-reactions among variants and the truly type-specific responses. A refined understanding of cross-reactive antibody binding could guide the selection of the most informative subsets of variants for diagnostics and multivalent subunit vaccines. We explored the antibody binding reactivity of sera from human patients and Peromyscus leucopus rodents infected with Borrelia burgdorferi to the polymorphic outer surface protein C (OspC), an attractive candidate antigen for vaccine and improved diagnostics for Lyme disease. We constructed a protein microarray displaying 23 natural variants of OspC and quantified the degree of cross-reactive antibody binding between all pairs of variants, using Pearson correlation calculated on the reactivity values using three independent transforms of the raw data: (1) logarithmic, (2) rank, and (3) binary indicators. We observed that the global amino acid sequence identity between OspC pairs was a poor predictor of cross-reactive antibody binding. Then we asked if specific regions of the protein would better explain the observed cross-reactive binding and performed in silico screening of the linear sequence and 3-dimensional structure of OspC. This analysis pointed to the C-terminal helix of the structure as a major determinant of type-specific cross-reactive antibody binding. We developed bioinformatics methods to systematically analyze the relationship between local sequence/structure variation and cross-reactive antibody binding patterns among variants of a polymorphic antigen, and this method can be applied to other polymorphic antigens for which immune response data is available for multiple variants. Antibody profiling was performed on sera from Borrelia burgdorferi infected and non-infected humans and Peromyscus leucopus rodents against 23 variants of the surface protein OspC . For infected human serum samples, the OspC type of the infecting B. burgdorferi strain is unknown; for experimentally-infected P. leucopus serum samples, it is known. Of human serum samples, 55 were from infected individuals and 25 from naive controls. Of P. leucopus serum samples, 23 were from infected individuals and 7 were from naive controls.
2013-04-12 | E-GEOD-45996 | biostudies-arrayexpress
Project description:see publication, arrays from 4 XXY genotypes containing polymorphic Y chromosomes
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