A unified view is provided of how genome structure is established, how it relates to function, and how its disruption contributes to tumorigenesis, suggesting that alterations in genome structure can, in some contexts, actively reshape oncogenic programs.
Abstract
The three-dimensional (3D) genome provides an essential layer of organization that shapes genome function in space and time. Chromatin compartments and topologically associating domains (TADs) arise from the interplay between intrinsic properties of chromatin and architectural factors, including cohesin and CTCF. Despite substantial progress in defining these structural features, whether 3D genome architecture plays a causal role in regulating processes such as transcription, DNA replication, and DNA repair, or instead reflects underlying regulatory activity, remains unresolved. Here, we use the distinction between chromatin-intrinsic features and architectural factors as a framework to evaluate evidence for causality in genome structure-function relationships. We extend this framework to cancer, where both intrinsic alterations (including noncoding mutations, structural variants, and changes in chromatin state) and architectural factor perturbations (such as mutations in architectural proteins and dysregulation of transcriptional machinery) disrupt genome organization and contribute to disease progression. These findings suggest that alterations in genome structure can, in some contexts, actively reshape oncogenic programs. A major limitation in applying 3D genome insights to cancer biology is the cost and complexity of omics assays. Recent advances in artificial intelligence (AI) and machine learning (ML) enable inference and prediction of 3D genome organization from sequence and epigenomic features, providing insight into the extent to which genome folding is encoded intrinsically versus dynamically regulated in architectural factors. This perspective provides a unified view of how genome structure is established, how it relates to function, and how its disruption contributes to tumorigenesis.
Chromatin remodeling comprises a set of molecular mechanisms that regulate gene transcription, DNA replication, and DNA repair by altering nucleosome structure. Previous studies have found that chromatin remodelers are heavily mutated in cancer patients, and targeting aberrant chromatin remodeling activities holds great potential for clinical benefit. Despite these promising findings, several significant hurdles remain before this strategy can be successfully transitioned from bench to bedside. The classic concept of chromatin remodeling focuses on the linear 2D chromatin structural level. While the emergence of sophisticated sequencing modalities has underscored the significance of 3D chromatin architecture, the mechanistic underpinnings and broader implications for cancer biology continue to be largely elusive. This review provides a comprehensive synthesis of the mechanisms and functional roles of classical chromatin remodelers within both physiological and neoplastic contexts. Furthermore, we integrate emerging insights regarding the cohesin complex as a primary mediator of three-dimensional (3D) genomic organization. By proposing a hierarchical framework that distinguishes between 'first-level' (classical) and 'higher-order' chromatin remodeling, we aim to provide a more holistic understanding of the integrated regulatory networks governing chromatin architecture. Furthermore, we have systematically cataloged the landscape of therapeutic strategies targeting chromatin remodelers in oncology. By evaluating the divergence between clinically approved therapies and those currently in developmental pipelines, we delineate the primary challenges confronting the field and propose strategic directions for future research. Collectively, we have delineated the multifaceted contributions of chromatin remodeling to cancer progression. The strategic modulation of these remodeling processes represents a vital frontier in the development of novel therapeutic interventions and is likely to emerge as a primary focus for future cancer management strategies.
Three-dimensional (3D) chromatin structure is crucial for gene regulation and cellular identity, with alterations in this structure being closely associated with tumor development. Although the research of tumor genomics has made significant progress in the past decade, the mechanism of 3D chromatin structure in tumorigenesis is not completely clear. Recent studies have shown that the distortion of chromatin spatial conformation has become one of the core factors driving normal cell carcinogenesis by changing the gene regulatory network. Abnormal high-order chromatin organization leads to abnormal activation of oncogenes or silencing of tumor suppressor genes. This 3D chromatin disorder has been confirmed to be directly related to the phenotypic plasticity of a variety of tumors. Therefore, the dynamic changes of 3D chromatin structure play a key role in the occurrence and development of tumors, especially for malignant tumors with difficult diagnosis and lack of treatment. This article provides an overview of hierarchical alterations in cancer 3D chromatin structure, the mechanisms governing these changes, recent advances in detection technologies, and emerging therapeutic strategies. The unique 3D chromatin variation pattern in cancers may become a new biomarker and provide a theoretical basis for epigenetic therapy targeting chromatin spatial organization. In the future, integrating multi-omics data to develop specific drugs for key nodes of the 3D chromatin and establishing an early diagnosis system based on spatial chromatin characteristics will become an important direction to break through the bottleneck of cancer treatment.
Yang Liu, Minghua Wu· Cell Communication and Signa...· 0 citations
G-quadruplexes (G4s) are essential regulatory structures whose biological functions are inseparable from their potential to destabilize the genome. They play critical roles in transcription, replication and chromatin architecture, yet they also contribute to the genomic instability that fuels cancer. This dual role is an inherent consequence of where G4s form in the genome. G4s are enriched at highly active regulatory regions, including promoters, replication origins and topologically associated domain boundaries, where their controlled formation and resolution by helicases and topoisomerases support normal genome function. When this control is lost, the same features that make G4s functional become harmful, leading to R-loop and G-loop accumulation, replication fork stalling and increased conflicts between transcription and replication. Topoisomerase activity, which normally relieves supercoiling stress, can instead generate the DNA double-strand breaks that characterize cancer genomes. Persistent G4 structures also promote micronuclei formation and cytoplasmic DNA accumulation, activating the cGAS-STING innate immune signaling pathway. Here, we discuss these mechanisms and present pan-cancer genomic analyses showing that these processes operate broadly across human tumors. Therapeutically targeting G4s requires balancing their essential regulatory roles with their pathological effects. Understanding this tension is therefore essential for exploiting G4s as therapeutic targets across cancer types.
Anna R. Bartosik, Magda Bujnowska, D. B. Stovall et al.· Critical reviews in biochemi...· 0 citations
A new machine-learning framework aims to improve the success rate of computational protein design while moving away from results that reproduce sequences found in nature.
