Dynamic three-dimensional chromatin remodeling in lung disease: mechanistic principles, pathogenic regulatory networks, and translational challenges.

Three-dimensional (3D) chromatin architecture provides a spatial framework through which genomic sequences, epigenetic states, transcription factors, and distal regulatory elements are integrated to control cell type-specific gene expression. Increasing evidence suggests that disruption of this organization contributes to abnormal transcriptional programs in lung development and disease. In this review, we provide a mechanism-centered synthesis of 3D genome regulation in pulmonary biology, focusing on hierarchical features including A/B compartments, topologically associating domains, chromatin loops, and enhancer-promoter interactions. We discuss how architectural proteins, transcription factors, epigenetic modifications, and regulatory RNAs influence these structures and examine their involvement in chronic obstructive pulmonary disease, pulmonary fibrosis, lung cancer, and developmental lung abnormalities. Particular emphasis is placed on distinguishing direct evidence of altered chromatin architecture from changes in chromatin accessibility, transcription-factor activity, or epigenetic state that provide regulatory context but do not independently demonstrate 3D genome remodeling. Cross-disease comparison reveals both shared and context-dependent mechanisms, with altered long-range regulatory communication emerging as a recurrent feature while the relevant architectural scale, regulatory factors, cell types, and phenotypic consequences remain disease specific. We further discuss current limitations, including cellular heterogeneity, limited temporal resolution, and the challenge of establishing causality from static interaction maps. Advances in cell type-resolved chromatin conformation profiling, spatial multi-omics, live-cell imaging, and targeted perturbation should enable more precise mechanistic models and clarify whether disease-associated chromatin interactions can ultimately support patient stratification and therapeutic intervention in pulmonary disease.