Multi-layered gene regulation by long non-coding RNAs: from chromatin to genome architecture

Long non-coding RNAs (lncRNAs) are now recognized as pivotal regulators that enable the fine-tuned control of gene expression. While the functional diversity of lncRNAs challenges comprehensive understanding of their mechanisms, recent advances have revealed how these molecules coordinate epigenomic control, ranging from local chromatin regulation to large-scale nuclear organization. By scaffolding, recruiting, or antagonizing transcription factors and chromatin-modifying complexes, lncRNAs shape chromatin states, including histone modifications and DNA methylation patterns. In parallel, lncRNAs regulate three-dimensional genome architecture by modulating chromatin loops, topologically associating domains, and nuclear compartments. These regulatory mechanisms frequently operate in a coordinated manner, as exemplified by X chromosome inactivation, in which lncRNAs direct chromosome-wide silencing through combined epigenetic reprogramming and architectural remodeling. This review synthesizes current mechanistic insights into how lncRNAs integrate epigenetic modification with architectural regulation to achieve spatiotemporal gene expression, and highlights how lncRNA dysregulation contributes to human disease. We provide an integrative perspective on how lncRNAs link epigenetic programs with genome topology to control normal physiology and pathogenesis. [BMB Reports 2026; 59(2): 112-123].