Highly efficient chromatin conformation capture with post-enrichment in single cells by HiChew

Abstract We present HiChew, a novel chromatin conformation capture method combining efficient sticky-end ligation with post-PCR methylation-based enrichment. HiChew achieves approximately 50% valid pair ratios compared to 8% for unenriched methods, while maintaining high sensitivity. Its single-cell implementation, snHiChew, achieves 45–50% valid pair ratios, and enables 5–10 kb resolution mapping with 70–80% bin coverage. Comparative analyses show strong concordance with conventional Hi-C for chromatin compartments, TADs, and loops. By combining scalability, cost-effectiveness and data quality, HiChew provides a powerful platform for advancing studies of 3D genome architecture analysis.