A comprehensive synthesis of the mechanisms and functional roles of classical chromatin remodelers within both physiological and neoplastic contexts is provided and a hierarchical framework that distinguishes between 'first-level' and 'higher-order' chromatin remodeling is proposed.
Abstract
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.
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.
Rebecca G. Smith, Hannah M. Wilson, Kathleen L. Schiela et al.· Genes & Development· 0 citations
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
The findings uncover a non-canonical mechanism whereby a chromatin remodeler regulates transcription primarily through three-dimensional genome organization rather than local accessibility control, and establish histone modification-guided chromatin remodeling as a key principle in gene regulation.
Ming Yu, Jingdong Xue, Qi Zhang et al.· bioRxiv· 0 citations
In a recent study published in Nature, Chen et al. introduced CHARM (single-cell assay for Chromatin conformation, Histone modi fi cation, chromatin Accessibility, and RNA expression Multi-omics pro fi ling), a platform that simultaneously captures four regulatory modalities within the same nucleus. 1 This integrated strategy provides a comprehensive framework for dissecting how multiple layers of epigenetic regulation converge to control gene expression at single-cell resolution. Gene regulation in eukaryotic cells is governed by a complex interplay of molecular and spatial mechanisms. Chromatin accessibility determines whether regulatory elements such as promoters and enhancers are available for transcription factor binding. Histone modi fi cations de fi ne chromatin states that either promote or repress transcription. In parallel, the three-dimensional organization of the genome establishes spatial proximity between distal regulatory elements and their target genes. Although each of these regulatory layers has been extensively studied, understanding how they operate together within the same cell has remained a major challenge. 2 Previous technologies have provided valuable insights into individual modalities. ATAC-seq pro fi les chromatin accessibility, CUT&Tag captures histone modi fi cations, and Hi-C reveals three-dimensional genome architecture. Recent single-cell platforms such as ChAIR and scHiCAR jointly pro fi le chromatin accessibility, RNA, and 3D contacts, but their 3D contact capture is anchored at accessible chromatin or candidate cis-regulatory elements, introducing structural bias into chromatin architecture reconstruction. 3,4 Moreover, regulatory modalities not captured by these platforms, such as histone modi fi cations, require separate pro fi ling and computational integration for broader cross-modality analysis. CHARM is distinguished from previous platforms by adding histone modi fi cation as a fourth same-cell modality and by using restriction-enzyme-based Hi-C
Hakjin Kim, Jongwon Byun, Taeho Kwon· Signal Transduction and Targ...· 0 citations
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