Looplook: An integrative suite for target assignment and functional annotation of chromatin interactions empowered by expression-aware refinement and connected components clustering

MotivationLinking distal cis-regulatory elements (CREs) to their cognate target genes remains a fundamental challenge in functional genomics. While advances in chromosome conformation capture technologies have substantially uncovered 3D chromatin architectures, versatile auxiliary tools for the spatial annotation of linear genomic features remain limited. Existing pipelines primarily focus on basic topological assignments, often lacking the flexibility to integrate diverse, user-defined multi-omics datasets. Furthermore, conventional topology-only strategies assume all physical contacts are functionally active, an oversight that frequently generates massive false-positive target assignments. Consequently, there is a compelling need for a versatile computational framework that systematically reconciles physical 3D proximities with dynamic transcriptional outputs. ResultsTo address these limitations, we present looplook, an end-to-end integrative suite designed to reconstruct high-confidence spatial regulatory networks from complex chromatin topologies and to enable automated functional inference. Looplook provides four core capabilities: (1) robust consensus building for denoising and consolidating replicated or multi-source chromatin loop by employing connected component clustering; (2) bidirectional spatial annotation between 3D chromatin loops and diverse linear genomic features, offering optional graph-based high-order discovery and a smart linear fallback for gapless network resolution; (3) a transcriptome-guided refinement algorithm which systematically eliminates transcriptionally silent false positives; and (4) automated downstream functional profiling seamlessly integrated with customizable multi-track visualization. A case study of the FOSL2- and BRD4-dependent network in liposarcoma cells demonstrated that looplook, through its expression-aware topological refinement, significantly enhances functional signal-to-noise ratios and captures cistromes with higher responsiveness to BRD4 degradation. By distilling raw physical contacts into biologically meaningful networks, looplook provides a powerful and accessible toolkit for exploring high-order gene regulation. Availability and ImplementationLooplook is freely available as an open-source R package at [https://github.com/zying106/looplook], accompanied by comprehensive documentation and tutorials.