3D chromatin structure in chondrocytes identifies putative osteoarthritis risk genes

Author:

Thulson Eliza1ORCID,Davis Eric S2ORCID,D’Costa Susan3ORCID,Coryell Philip R3ORCID,Kramer Nicole E2ORCID,Mohlke Karen L4ORCID,Loeser Richard F35ORCID,Diekman Brian O367ORCID,Phanstiel Douglas H12378ORCID

Affiliation:

1. Curriculum in Genetics and Molecular Biology, University of North Carolina , Chapel Hill, NC 27599, USA

2. Curriculum in Bioinformatics and Computational Biology, University of North Carolina , Chapel Hill, NC 27599, USA

3. Thurston Arthritis Research Center, University of North Carolina , Chapel Hill, NC 27599, USA

4. Department of Genetics, University of North Carolina , Chapel Hill, NC 27599, USA

5. Division of Rheumatology, Allergy and Immunology, University of North Carolina , Chapel Hill, NC 27599, USA

6. Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University , Raleigh, NC 27695, USA

7. Lineberger Comprehensive Cancer Center, University of North Carolina , Chapel Hill, NC 27599, USA

8. Department of Cell Biology and Physiology, University of North Carolina , Chapel Hill, NC 27599, USA

Abstract

Abstract Genome-wide association studies have identified over 100 loci associated with osteoarthritis risk, but the majority of osteoarthritis risk variants are noncoding, making it difficult to identify the impacted genes for further study and therapeutic development. To address this need, we used a multiomic approach and genome editing to identify and functionally characterize potential osteoarthritis risk genes. Computational analysis of genome-wide association studies and ChIP-seq data revealed that chondrocyte regulatory loci are enriched for osteoarthritis risk variants. We constructed a chondrocyte-specific regulatory network by mapping 3D chromatin structure and active enhancers in human chondrocytes. We then intersected these data with our previously collected RNA-seq dataset of chondrocytes responding to fibronectin fragment, a known osteoarthritis trigger. Integration of the 3 genomic datasets with recently reported osteoarthritis genome-wide association study variants revealed a refined set of putative causal osteoarthritis variants and their potential target genes. One of the putative target genes identified was SOCS2, which was connected to a putative causal variant by a 170-kb loop and is differentially regulated in response to fibronectin fragment. CRISPR-Cas9-mediated deletion of SOCS2 in primary human chondrocytes from 3 independent donors led to heightened expression of inflammatory markers after fibronectin fragment treatment. These data suggest that SOCS2 plays a role in resolving inflammation in response to cartilage matrix damage and provides a possible mechanistic explanation for its influence on osteoarthritis risk. In total, we identified 56 unique putative osteoarthritis risk genes for further research and potential therapeutic development.

Funder

NIH

Publisher

Oxford University Press (OUP)

Subject

Genetics

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