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.
Heterochromatin marked by histone H3 lysine 9 di- or trimethylation (H3K9me2/3) underpins transcriptional silencing and nuclear organization, yet its full complement of associated proteins remains incompletely defined. Here, we apply ChromID proximity labelling with the mouse HP1β chromodomains to map the H3K9me3-proximal proteome in Caenorhabditis elegans, recovering known heterochromatin factors alongside previously uncharacterized candidates. We pursued one such candidate, the vaccinia-related kinase VRK-1, because of its established but poorly understood links to chromatin organization. Intriguingly, VRK-1 dynamically relocates from a broad nuclear distribution to the nuclear periphery upon azide or heat stress. Following these stresses, bulk chromatin exhibits similarly increased peripheral enrichment and apparent compaction, as assessed by radial fluorescence profiles. Although VRK-1 is not necessary for stress-induced chromatin reorganization, decompaction and repositioning of chromatin away from the nuclear envelope during recovery requires VRK-1. VRK-1 depletion leads to persistent perinuclear chromatin retention and compromises post-stress survival. Furthermore, loss of VRK-1 catalytic activity results in over-retention of chromatin at the nuclear periphery under normal growth conditions; this phenotype can be reversed by depletion of a key VRK-1 substrate at the nuclear envelope BAF-1. Our findings identify VRK-1 as a key regulator that controls the interaction of chromatin with the nuclear lamina through regulation of BAF-1.
W. Smith, Valeryia Aksianiuk, Ramon Pfaendler et al.· bioRxiv· 0 citations
The coordinated activities of histone modifications and chromatin-associated proteins establish chromatin states that regulate genome function and cellular identity. However, the organizational principles that distinguish chromatin states across cell types remain incompletely understood. Here, we integrated genome-wide profiles of CTCF, H3K27ac, H3K9ac, H3K27me3, and H3K9me3 at 1-kb resolution to generate a unified representation of chromatin organization in human cells. Unsupervised embedding resolved five principal chromatin states corresponding to constitutive heterochromatin, CTCF-associated architectural chromatin, transcriptionally active chromatin, mixed repressive chromatin, and Polycomb-associated chromatin. Comparative analyses of HCT116 and K562 cells revealed that cell-type-specific epigenomic differences arise predominantly through remodeling of Polycomb-associated chromatin, whereas the remaining chromatin states exhibit broadly similar epigenomic signatures and comparatively limited remodeling. Consistent with this observation, principal component analysis identified H3K27me3 as the primary contributor to genome-wide epigenomic divergence, whereas CTCF represented a secondary contributor. Integration with Hi-C data further demonstrated that CTCF-associated chromatin is strongly enriched at chromatin loop anchors and other local architectural features, linking chromatin-state organization to three-dimensional genome architecture. Together, our findings identify distinct chromatin-state classes that organize the human epigenome and reveal Polycomb-associated chromatin as a key determinant of cell-type-specific epigenomic differences.
Joseph Martini, Ryan A. Williams, Rebecca G. Smith et al.· bioRxiv· 0 citations
Like heterochromatin protein 1 (LHP1) is a conserved HP1-like chromatin protein in land plants and a major Polycomb-associated factor that recognizes H3K27me3 enriched euchromatic domains. Recent biochemical, genomic, and structural studies show that LHP1 acts as a modular chromatin scaffold whose regulatory output depends on local histone modifications, RNA interactions, transcriptional factors, and PRC1/PRC2-associated partners. In this review, we outline emerging roles of LHP1 in Polycomb-mediated repression, chromatin-state maintenance, transcriptional responsiveness, hormone signaling, stress responses, and TE-proximal gene regulation. We also examine the structural features and evolutionary diversification of LHP1 homologs across land plants and assess how duplicated LHP1 copies may contribute to species-specific developmental and stress-adaptive traits. Rather than presenting LHP1 as a universal master regulator, we emphasize its context-dependent functions and distinguish experimentally supported mechanisms from correlative or still unresolved models. Finally, we highlight future directions involving genome editing, epigenomic profiling, chromatin conformation analysis, and targeted epigenome engineering to clarify how LHP1 associated modules may be exploited for crop improvement and postharvest quality management.
Rehman Sarwar, Xiang Fan, Ke Dong et al.· Physiologia Plantarum : An I...· 0 citations
ATP-dependent chromatin remodelers of the CHD family regulate genome organization and transcription, yet their dynamic behaviour in native chromatin remains unclear. Here, we performed in vivo single-molecule tracking of the CHD remodeler Hrp3 in live Schizosaccharomyces pombe cells to quantify its chromatin interaction dynamics. By generating domain-deletion mutants (Δchromo, ATPaseK406A (ATPase-dead), Δcoupling region, DNA binding domains (ΔSANT, ΔSLIDE), and ΔDUF), we systematically dissected the contribution of each domain to DNA binding in vivo. While some observations align with previous in vitro studies, key differences highlight the critical influence of the cellular chromatin environment on remodeler function. We find that Hrp3 exhibits specific binding only with constitutive heterochromatin, but not with euchromatin or facultative heterochromatin. We tested the effect of altered histone acetylation and methylation on the chromatin binding dynamics of Hrp3. Our data demonstrated the chromatin context-dependent binding of Hrp3: reduced acetylation allows binding of Hrp3 with euchromatin, increased acetylation reduces binding of Hrp3 with heterochromatin, and reduced methylation increases the binding of Hrp3 with heterochromatin. Interestingly, we found specific binding of Hrp3 with mitotic chromosomes, suggesting its role in maintaining heterochromatin silencing during mitosis and probably contributing to epigenetic memory. Collectively, our results demonstrate that Hrp3 chromatin binding is highly sensitive to epigenetic modifications and chromatin compaction and cannot be fully predicted from in vitro studies alone. Given the conservation of CHD remodelers and their links to human diseases, this study provides important insights into how epigenetic therapies, such as HDAC inhibitors, may modulate chromatin remodeler dynamics and influence gene expression.
Akriti Kumari, Oankar Varde, Varsha Gopi et al.· Journal of Molecular Biology· 0 citations
These findings identify Uhrf1 as a central regulator that tightly couples DNA methylation maintenance to 3D genome organization during gastrulation, thereby, directing early lineage specification and positioning Uhrf1 as a pivotal mediator of epigenetic information transfer during early embryogenesis.
Agata Kurowski, Bohan Zhu, Yifei Sun et al.· bioRxiv· 0 citations
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.
