Metabolic disruptions through a three-dimensional genomic lens

Chromatin architecture - encompassing epigenetic states and three-dimensional (3D) nuclear organization - operates at the interface of genotype, cellular metabolism, and transcriptional regulation. Chromatin loops physically connect gene promoters with distal regulatory elements, providing a structural basis through which non-coding genetic variants modulate target gene expression and contribute to metabolic disease risk. Although the precise mechanisms linking loop dynamics to transcriptional output remain incompletely understood, 3D genomic approaches are rapidly advancing our ability to interpret non-coding variation in disease. Beyond genetic predisposition, chromatin architecture responds dynamically to environmental signals, including diet and circadian oscillations, in a cell-type-specific manner. Here, we review recent advances in mammalian 3D chromatin biology and their implications for transcriptional regulation in metabolic health and disease.