Background and Significance:
Genome-wide association studies (GWAS) have revealed thousands of variants associated with complex traits and diseases, but most of these variants lie in non-coding regions, making it difficult to identify their functional targets. The three-dimensional (3D) organization of chromatin plays a crucial role in gene regulation by bringing enhancers and promoters into physical proximity. High-resolution mapping of this chromatin architecture is therefore essential for linking non-coding variants to their regulatory genes and understanding disease mechanisms.
Methodology:
To address this, we employed Dovetail Micro-C, a micrococcal nuclease–based chromatin conformation capture technique that enables nucleosome-level resolution of chromatin interactions. Primary human osteoclasts were differentiated from monocytes obtained from four healthy donors and subjected to Micro-C sequencing to generate a comprehensive 3D genome interaction map. The resulting contact data were integrated with transcriptomic, epigenomic, and GWAS datasets for bone mineral density and skeletal traits.
Major Findings:
Micro-C analysis yielded over 69 million chromatin interactions and identified more than 16,000 osteoclast-specific chromatin loops not present in precursor cells. These loops revealed enhancer–promoter contacts connecting non-coding GWAS variants with putative regulatory genes. Functional enrichment analyses showed significant involvement of pathways regulating osteoclast differentiation, Wnt signaling, and bone remodeling.
Conclusion:
This study demonstrates the utility of Micro-C as a discovery platform for interpreting non-coding GWAS signals by revealing the 3D regulatory framework of disease-relevant cell types. The generated high-resolution chromatin topology map of human osteoclasts provides a valuable resource for elucidating how genetic variation influences gene regulation and contributes to skeletal disease susceptibility.