The clinical significance of regulatory variants at the GDF5 locus in joint disease
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ABSTRACT:
PROVIDER: PRJNA641883 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12091600_1.fastq.gz | Fastqsanger.gz | |||
| SRR12091600_2.fastq.gz | Fastqsanger.gz | |||
| SRR12091601_1.fastq.gz | Fastqsanger.gz | |||
| SRR12091601_2.fastq.gz | Fastqsanger.gz | |||
| SRR12091602_1.fastq.gz | Fastqsanger.gz |
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Project description:Genetic variants in cis-regulatory regions of GDF5 can lead to common joint diseases with high degrees of joint specificity.
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Project description:Objective: Joint formation begins with the establishment of an interzone within the cartilaginous anlagen of the future skeleton and both Gdf5 and Erg are proposed as regulators of chondrocyte differentiation during and post interzone formation. The aim of this study was to examine the relationship between Gdf5 and Erg expression and downstream effects on chondrocyte gene expression. Design: Erg expression was identified in mouse knee joints at E13.5. Expression and microarray analyses were performed using micromass cultures of murine C3H10T1/2 mesenchymal cells undergoing induced chondrogenesis in the presence of absence of Gdf5 and Erg. Results: At E13.5, Erg expression was found to surround epiphyseal chondrocytes and span the interzone up to the intermediate zone. Erg splice forms were expressed in micromass cultures, and their expression profile was altered by the addition of recombinant Gdf5 depending on the stage of differentiation. Overexpression of Erg-010 resulted in a downregulation of Col2a1 and Col10a1. Microarray analysis following Erg-010 overexpression identified two potential downstream targets, Ube2b and Osr2, which were also differentially regulated by Gdf5. Conclusion: Erg regulation by Gdf5 in mesenchymal cells in vitro is dependent on the stage of chondrogenesis, and its expression in vivo demarcates chondrocytes that are not destined to be consumed by endochondral ossification. Functionally, Erg expression causes downregulation of Col2a1 and Col10a1 expression and this effect is potentially mediated by Osr2, which is a known regulator of chondrocyte differentiation. The identification of Ube2b as a putative downstream target of Erg-010 suggests that it may contribute to the regulation of the ubiquitination pathway and thereby BMP2 signaling, which is essential for normal knee joint development. RNA from overexpression experiments was extracted as described above. Total RNA quality was confirmed using a Bioanalyzer 2100 (Agilent). Labelled targets were generated from total RNA and hybridized to GeneChip Mouse Genome 430 2.0 arrays (Affymatrix) (Genomics Centre, University of Manchester). The raw fluorescence intensity values were normalized using a Robust Multi-array Average approach using dChip (V2005)
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Project description:Our prior work indicated that the transcription factor Creb5 plays a crucial role in the genesis of synovial joints. Here, we perform an integrative analysis of the transcriptome, chromatin accessibility, and Creb5-chromatin occupancy in Creb5-expressing synovial joint progenitor cells. This analysis revealed that Creb5 directly binds to both its own two promoters and to the regulatory regions of the early joint markers, Gdf5 and Sfrp2; each of whose expression in the joint-interzone is Creb5-dependent. Functional enhancer analysis indicated that Creb5 binding sites in its own two promoters are necessary for these sequences to drive transgene expression in a pattern that mimics endogenous Creb5 expression. While Creb5 directly regulates both Gdf5 and Sfrp2 expression in the inner joint-interzone by binding to either CREs or TREs in their regulatory elements, Creb5 activates Barx1 expression specifically in the outer joint-interzone; and thus initiates both the formation of the joint-interzone and regionalization of cell fates within this tissue.
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