Deciphering context-dependent epigenetic program by network-based prediction of clustered open regulatory elements from single-cell chromatin accessibility

Park, S.; Ma, S.; Lee, W.; Park, S. H.

doi:10.64898/2026.03.17.712366

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bioRxiv · 10.64898/2026.03.17.712366

Deciphering context-dependent epigenetic program by network-based prediction of clustered open regulatory elements from single-cell chromatin accessibility

Park, S.·Ma, S.·Lee, W.·Park, S. H.

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Abstract

Large cis-regulatory domains, spanning tens to hundreds of kilobases, are pivotal in orchestrating cell-state-specific transcriptional programs that define cellular identity. However, existing single-cell analytical frameworks lack the capacity to identify these higher-order structures, thereby obscuring the coordinated, domain-level epigenetic regulation essential for complex biological processes. To address this, we introduce enCORE, a computational framework that leverages enhancer-enhancer interaction networks to determine Clustered Open Regulatory Elements (COREs) solely from single-cell ATAC-sequencing data. Our approach faithfully recapitulates established hematopoietic hierarchies and resolves lineage-specific regulatory programs by recovering canonical master transcription factors, frequent chromatin interactions, and enrichment of fine-mapped immune-related disease-associated genome-wide association study (GWAS) variants. In colorectal cancer, enCORE captures tumor-associated H3K27ac landscapes and prioritizes USP7 as a potential therapeutic candidate, supported by in silico perturbation. Collectively, our framework provides a powerful and scalable platform for deciphering the complex epigenetic architectures underlying human development and disease.

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Park, S., Ma, S., Lee, W., Park, S. H.. 2026-03-18. Deciphering context-dependent epigenetic program by network-based prediction of clustered open regulatory elements from single-cell chromatin accessibility. https://doi.org/10.64898/2026.03.17.712366

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