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Analysis of 3D Chromatin Structure in Chondrocytes Identifies Putative OA Risk Genes

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200345 | GEO | 2022/09/07

REPOSITORIES: GEO

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Analysis of 3D Chromatin Structure in Chondrocytes Identifies Putative OA Risk Genes

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