Rewiring cancer epigenome: lncRNA as modulator of chromatin architecture and neoplastic transformation

Epigenetic rewiring modulates gene expression by reshaping chromatin architecture without altering the underlying DNA sequence. The eukaryotic genome is intricately folded within a dynamic three-dimensional nuclear architecture, which is vital for maintaining genomic integrity and ensuring spatially precise gene regulation. Long non-coding RNAs (lncRNAs), a class of regulatory transcripts, play a pivotal role in organizing nuclear structure, preserving cell identity, and sustaining complex regulatory networks. Through interactions with DNA, RNA, transcription factors, and chromatin-modifying complexes, lncRNAs influence the formation and maintenance of higher-order chromatin structures, including topologically associating domains (TADs), lamina-associated domains (LADs), and chromatin loops. These structural frameworks facilitate or constrain long-range genomic interactions, thereby governing transcriptional programs. Aberrant lncRNA expression disrupts this regulatory architecture and is increasingly recognized as a driving force in oncogenesis. Notable lncRNAs, such as XIST, HOTAIR, and MALAT1, modulate gene expression by recruiting epigenetic regulators, including Polycomb Repressive Complex 2 (PRC2), which alters histone modifications and DNA methylation landscapes, and rewires enhancer-promoter contacts. These mechanisms underlie profound transcriptional reprogramming in cancer cells. Technological advances in genome conformation capture methods (e.g., Hi-C, 3C) have enabled high-resolution mapping of these dynamic chromatin interactions, revealing the extent of lncRNA-mediated 3D genome remodeling in malignancy. This review synthesizes emerging evidence on the role of lncRNAs in shaping nuclear architecture and gene regulation, with a focus on their oncogenic and tumor-suppressive functions. By integrating insights into chromatin topology and epigenetic control, we underscore the potential of targeting lncRNAs and associated chromatin remodeling pathways as innovative diagnostic and therapeutic strategies in cancer and other complex diseases.