Recent studies suggest that molecular-scale organization of chromatin near the nuclear periphery (lamina-associated domains, LADs) affects gene regulation, providing transciptional supression, but the

The gap

Consensus across the literature

Supporting evidence — 6 representative gaps

• The Fluid Mosaic Model of chromatin organization: integrating dynamics, conformational heterogeneity and multiscale organization (2026) · doi

  compartments, with chromatin compartments being stable above the chromatin length of 10–25 kb26. Physical existence of these two types of compartments at individual chromosome level was revealed by elegant microscopy-based experiments27. Overall, compartments not only organize the chromatin based on its physiochemical properties but also based on its transcriptional state, although the two aspects may be coupled. Chromatin domains/TADs, separated by boundary regions, represent the fundamental unit of higher-order chromatin organization. They have been detected across species from yeast to humans2–4,25,28–30. Therefore, the formation of these domains appears to be a conserved feature of higher- order chromatin organization. Chromatin domains are formed by pre- ferential interactions within a contiguous region of chromatin as compared to neighboring regions on either side, ranging in size from tens to hundreds of kb. To understand how these chromatin domains arise, it is important to know the forces and mechanics which stabilize them. DNA and histone proteins, the primary components of chromatin, play an inherent role in formation of chromatin domains. As the sequence of bases A, T, G, C varies across genome, the composition (AT:GC) of DNA also varies, consequently the properties of DNA, such as its stiffness/flex- ibility and the probability of forming secondary topological structures also vary31. These properties of DNA can influence the very first level of chro- matin organization, i.e., formation of nucleosomes which requires wrapping of DNA around an octamer of histone proteins. It has been observed that some sequences are more favorable for formation of nucleosomes than others32. Flexibility of linker DNA between nucleosomes also influences chromatin folding. Distinct DNA topology near transcription start sites has been observed in yeast and many of these sites correspond to chromatin domain boundaries33. Intra-TAD organization, nuclear condensates, and interchromosomal interactions also seem to correlate with flexibility of DNA determined by the GC content34. In addition to its biomechanical properties, different DNA sequence motifs provide binding sites for various transcription factors and insulator proteins, which shape the architecture of chromatin35. Formation of nucleosomes along the DNA provides the first level of packaging in multiscale chromatin organization. Formation of nucleosomes results in the emergence of new set of biomechanical properties which influence the next levels of chromatin folding29,36. We and others have shown that the distribution of nucleosomes along the genome impact the formation of chromatin domains, domain boundaries, contacts along the length of chromosome and interchromosomal contacts. Change in dis- tribution (spacing) of nucleosomes alters the stiffness of chromatin, there- fore, changing the probability of formation of chromatin contacts. Furthermore, physiological linker lengths of chromatin fiber were foun

  Keywords: chromatin formation nucleosomes domains properties organization compartments level based proteins sites along contacts length chromosome
• The Fluid Mosaic Model of chromatin organization: integrating dynamics, conformational heterogeneity and multiscale organization (2026) · doi

  https://doi.org/10.1038/s42003-026-10052-y Fig. 1 | Nanoscale organization of chromatin. Super-resolution images showing organization of chromatin into domains of varying size and density. a Distribution of histone H2B in Hela cells detected by photoactivated localization microscopy (PALM) and corresponding image of DNA stained with Hoechst stain50. b Distribution of histone H2B in human fibroblast cells detected by stochastic optical reconstruction microscopy (STORM), showing nanoscale chromatin domains49. Adopted with permission from Elsevier (Authorization Ref. Nos. 5973370305590 and 6005870027166). Fig. 2 | Fluid Mosaic Model of chromatin. Mosaic organization of chromatin within the cell nucleus, “chromatin bodies” (droplets) of varying sizes (clutches, domains, lamina associated domains (LADs), compartments) floating in the nucleo- plasm, coalescing and dissolving. structural changes observed in nucleosomes. According to an analysis, only 1–2 kBT of energy are required for unwrapping of first 25 bp of DNA, making the nucleosome exist in a partially unwrapped state for about 10–30% of the time56. Sub-nucleosomal structures, hexasomes, have been identified within the cell nucleus57 and a nucleosome conformation in which H2A:H2B dimer dissociates from the octamer and remains associated with the partially unwrapped DNA has been estimated to populate for 0.2–3% of the time58. Therefore, nucleosomes seem to possess significant intrinsic dynamics. Single nucleosome imaging of live cells has shown that nucleosomes are in a steady-state sub-diffusive spatial motion within a constrained space with a radius of about 150 nm. This motion was observed within a timescale of <1 s and was independent of the stage of the cell cycle or the volume of the nucleus. Interestingly, this motion appears to be a mani- festation of thermal fluctuations, implying that nucleosomes can access a volume comparable to that occupied by a chromatin domain, 100–300 nm in diameter59. Nucleosome clutches varying in size from 2–10 nucleosomes have been observed in yeast, mouse and human cells49,51,52. Super-resolution live cell imaging revealed a coherent sub-diffusive dynamics of nucleosomal domains about 160 nm in diameter within a timescale of 500 ms. Remarkably, individual nucleosomes and their respective domains exhib- ited correlated motion, with slower dynamics observed in domains located toward the nuclear periphery and in heterochromatin. The dynamics also varied depending on the cell state and molecular crowding50. Although the influence of molecular crowding on chromatin organization is clear60–62, a model of chromatin organization that encompasses the crowded nucleo- plasm is lacking. Inter-nucleosomal interactions, biochemical states of histones, cohe- sin, PcG proteins, HP1 etc., seem to contribute to stability and dynamics of chromatin domains. Intrinsic nucleosome fluctuations foster formation of heterogeneous chromatin domains by promoting multivalent inter- nucleosomal interactions63. Increasing probability of multivalent inter- nucleosome interactions by embedding a compact tetra-nucleosome into a chromatin condensate results in its partial unfolding, suggesting nucleo- somal crowding itself can generate heterogeneous chromatin domains64. Modulating the internucleosome interactions by altering acetylation of histones strongly influences the dynamics and size of chromatin domains. Inhibition of deacetylation results in destabilization of chromatin domains and an increase in nucleosome dynamics within the nucleus50. Cohesin and HP1 seem to act as molecular glues, dampening the dynamics of nucleo- somes and stabilizing chromatin domains38,50. Interestingly, nucleosome spacing significantly influences the formation of nucleosome domains, with native linker lengths promoting the formation of chromatin domains50,64. Multivalent internucleosome interactions are believed to lead to the for- mation of chromatin domains by LLPS, and chromatin-associated proteins like HP1 promote the process of LLPS50,63. Polycomb group proteins, forming nanoscale sub-nuclear clusters, compact chromatin by self- association of polycomb repressive complex 1 (PRC1)39,65 and their phase separation property40,41. In parallel, RNA polymerase and transcription factors and coactivators also promote the formation of distinct chromatin to be driven by their phase separation domains which appears Communications Biology | (2026) 9:541 4 https://doi.org/10.1038/s42003-026-10052-y

  Keywords: chromatin domains nucleosome dynamics within nucleosomes organization cell interactions cells nucleus nucleo observed nucleosomal motion
• The Fluid Mosaic Model of chromatin organization: integrating dynamics, conformational heterogeneity and multiscale organization (2026) · doi

  Fig. 5 | Dynamical heterogeneity of chromatin across the nucleus. Variation in the magnitude of chromatin dynamics at different length scales across nucleus, from micrometer to nanometer scale, becomes evident with increasing resolution. Like the dynamic organization of membranes, with domains of varying sizes fusing and dissolving to achieve functionality18,19, the organization of chromatin is also dynamic and conformationally heterogeneous. It appears that the energy landscape of chromatin is highly rugged with many minima of variable energy depths, and transitions among many but not all of them are driven by thermal fluctuations. As depicted in Fig. 3, at a given energy basin in the broad energy landscape of the nucleus, the 11 nm nucleosome fiber lies on the brim, neighboring nucleosomes interact to form “clutches”, moving down the wall of the energy basin, nucleosome clutches coalesce into chromatin domains and chromatin domains coalesce into compart- ments, and finally into chromosomes, occupying the bottom of the basin. Clutch formation can initiate from anywhere on the brim, and nucleosome fiber can take multiple routes to reach the bottom of the basin. Clutches/ domains can hop and fuse in multiple ways and give rise to different con- formations of chromatin. This can explain the observed cell-to-cell con- formational heterogeneity of chromatin. It may also be possible that even multiple clutches along the length of the chromatin fiber may form simultaneously and coalesce with time. The path from brim to bottom of the basin seems to be a rugged, resulting in population of metastable inter- mediate structures (Fig. 3). Progressive fusion/coalescence of chromatin structures into bigger ones may be driven by enthalpic and entropic con- tributions as well as by active processes. Depletion forces, which arise because of the differential sizes of molecules and macromolecular assemblies can also contribute to progressive coalescence of chromatin domains. The formation of larger chromatin domains causes an increase in the volume available to smaller molecules due to the overlap of exclusion volume of chromatin domains upon self-association. This seems to be entropically favored as it appears to increase the overall entropy of the system. Although, there is loss of mixing entropy upon coalescence, due to an increase in the volume available to smaller molecules their configurational freedom increases resulting in a net increase of entropy91,92. Parallel to the conformational landscape, a dynamical heterogeneity landscape exists. Broadly, dynamics appear to be faster in the center of the nucleus and slower near the periphery, due to association of chromatin with nuclear lamina93–96. Analogous to membrane domains stabilized by the actin cytoskeleton19, there exist lamina-associated domains of chromatin94. On a more detailed scale, heterochromatin regions show slower dynamics com- pared to euchromatin. At sub-micron scale, considerable dynamical het- erogeneity exists across the nucleus, with spots of slower and faster dynamics50,97. This dynamical heterogeneity landscape may evolve with time and in response to intra- or extracellular cues (Fig. 5).

  Keywords: chromatin domains nucleus energy landscape basin dynamical heterogeneity dynamics clutches increase across scale nucleosome brim
• The Fluid Mosaic Model of chromatin organization: integrating dynamics, conformational heterogeneity and multiscale organization (2026) · doi

  organization61,62,98,99, thus providing a holistic understanding at the nuclear scale. This model connects chromatin organization and the nucleoplasm, therefore, explaining chromatin organization in a more realistic context. Taken together, according to this model, chromatin exists in multiscale mosaic structures formed by preferential molecular interactions and energy- dependent processes, embedded in the nucleoplasm, with exchange of components between the two. All these features of the model supported by a large body of evidence obtained from in silico, in vitro, and in vivo studies by applying a diverse set of methods, as described above. The fluid nature can explain metastability and conformational heterogeneity of chromatin structures, and therefore the plasticity of chromatin required to regulate genome function. Integrating dynamics with organization may provide answers to phenomena like transcriptional bursting100, the observation of discordance between chromatin organization and gene expression101 etc. Although attempts have been made to connect organization and function90, in most of the studies, the focus has been on studying the conformation of chromatin (DNA)2–4,6,7,25,28,29, lacking the inherent dynamics aspect. The regulation of gene expression may be better understood if the relation between the “persistence time” of chromatin conformations is correlated with the level of gene expression rather than relying solely on a static view of chromatin organization. Moving forward, attaining a holistic understanding of chromatin behavior would require the integration of mosaic and fluid properties of chromatin. The mosaic property includes heterogeneity in composition and conformation, which is evident in different TADs (e.g., active and inactive TADs) along the genome and from single-cell experiments. The functional output of the genome, such as gene expression, is driven by both chromatin and its associated proteins together. Therefore, developing a more precise understanding of nuclear functioning demands the generation of ultra- high-resolution knowledge about the composition and spatial arrangement of chromatin and various chromatin-associated proteins with respect to each other in a locus-specific (domain-specific) manner across the genome using integrated structural biology approaches. Combining this information with Hi-C and ChIP-seq data would provide a precise genome-wide molecular interaction framework and hence the “physical” arrangement of chromatin. The next important step would be to study the dynamics of chromatin domains in live cells using high-resolution optical microscopy. Their “persistence time/meta-stability” may be an important factor in reg- ulating the function of underlying genomic loci. A vision for the future would be to integrate the molecular interaction framework and dynamics information to develop a “3D nucleome code” using high-power compu- tational architectures, which can ultimately be employed to build an in silico “virtual nucleus” with the appropriate inclusion of nucleoplasm and nuclear confinement/lamina effects. This would provide an invaluable platform to test the impact of various perturbations observed in different diseases and disorders on the organization and function of genome. In contrast to commonly carried reductionistic simulations, simulations on a “virtual nucleus” would provide a more holistic understanding with more accurate predictions. Achieving this relatively distant vision demands a concerted effort involving structural biology-based methods like cryo-EM/ET, geno- mics, live cell imaging, and high-power computational architectures. Received: 8 November 2025; Accepted: 1 April 2026;

  Keywords: chromatin organization genome understanding function dynamics provide gene expression high holistic nuclear model nucleoplasm mosaic
• Cancer epigenetics: from laboratory studies and clinical trials to precision medicine (2024) · doi

  ● Can the therapeutic efficacy of solid tumors be improved by combining therapies targeting different epigenetic mar- kers? ● Which changes measured in epigenetic cancer precision diagnosis and treatment are temporary, and which are true tumor biomarkers? ● How to compare the results in personalized treatment when the conclusions of laboratory studies and clinical studies are contradictory? INTRODUCTION Genomic DNA in eukaryotic cells is packaged around histones into a structure called the nucleosome, which further folds to produce the higher-order chromatin structure. Nucleosomes are the basic structural units of chromatin. They comprise of 146 bp of DNA wrapped in octamers of four core histones (H3, H4, H2A, and H2B dimers) [1]. The dynamic spatial organization of chromatin is critical for nucleosomes localization, the recruitment of transcrip- tional regulators, chromatin accessibility, and gene expression regulation. The compact spatial structure of nucleosomes exerts a universal inhibitory effect on mRNA transcription, whereas accessible spatial structure allows transcriptional regulators and RNA polymerases to access the DNA [2]. Changes to the chromatin structure are primarily regulated by epigenetic processes. Nucleo- some remodeling involved in higher order folding of chromatin fibers responds to changes in epigenetic modifications, including DNA methylation, histone modification and RNA-mediated processes [3]. Modifications of histone tails (primarily in chromatin fibers) act as expression or repression markers through the acetylation and methylation of many different amino acids [4]. Chromatin can store and transmit epigenetic codes in the form of DNA methylation or post-translational histone modifications [5]. These modifications are inherited during cell replication; therefore, epigenetic dysregulation is a feature of nearly all human cancers. More specifically, regulatory factors (coupled with an irregular 1Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, (Zhuhai People’s Hospital Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China. 2Department of Spinal Surgery, Yichang Central People’s Hospital Affiliated with China Three Gorges University, Yichang, Hubei 443000, China. 3Department of Pharmacy, Zhuhai People’s Hospital, Zhuhai People’s Hospital (Zhuhai Clinical Medical College of Jinan University), Zhuhai, Guangdong 519000, China. 4These authors contributed equally: Xinyang Yu, Hao Zhao. email: [email protected]; [email protected] ✉ Received: 13 October 2023 Revised: 23 December 2023 Accepted: 4 January 2024 Official journal of CDDpress 2 X. Yu et al. genome structure or abnormal gene expression) the transformation of various normal cell and tissue types into malignances. trigger Cancer is a multifactorial disease caused by genetic variation, epigenetic dysregulation, and environmental factors [6]. Ep

  Keywords: chromatin zhuhai epigenetic structure modi cations people hospital china changes treatment clinical nucleosomes spatial expression
• Nonspecific steric hindrance of protein particles by lamina-associated domains (2026) · doi

  Recent studies suggest that molecular-scale organization of chromatin near the nuclear periphery (lamina-associated domains, LADs) affects gene regulation, providing transciptional supression, but the biophysical mechanisms of supression behind remain unclear.

  Keywords: supression recent suggest molecular scale organization chromatin near nuclear periphery lamina associated domains lads affects