RESUMEN
The spatial segregation of pericentromeric heterochromatin (PCH) into distinct, membrane-less nuclear compartments involves the binding of Heterochromatin Protein 1 (HP1) to H3K9me2/3-rich genomic regions. While HP1 exhibits liquid-liquid phase separation properties in vitro, its mechanistic impact on the structure and dynamics of PCH condensate formation in vivo remains largely unresolved. Here, using a minimal theoretical framework, we systematically investigate the mutual coupling between self-interacting HP1-like molecules and the chromatin polymer. We reveal that the specific affinity of HP1 for H3K9me2/3 loci facilitates coacervation in nucleo and promotes the formation of stable PCH condensates at HP1 levels far below the concentration required to observe phase separation in purified protein assays in vitro. These heterotypic HP1-chromatin interactions give rise to a strong dependence of the nucleoplasmic HP1 density on HP1-H3K9me2/3 stoichiometry, consistent with the thermodynamics of multicomponent phase separation. The dynamical cross talk between HP1 and the viscoelastic chromatin scaffold also leads to anomalously slow equilibration kinetics, which strongly depend on the genomic distribution of H3K9me2/3 domains and result in the coexistence of multiple long-lived, microphase-separated PCH compartments. The morphology of these complex coacervates is further found to be governed by the dynamic establishment of the underlying H3K9me2/3 landscape, which may drive their increasingly abnormal, aspherical shapes during cell development. These findings compare favorably to 4D microscopy measurements of HP1 condensate formation in live Drosophila embryos and suggest a general quantitative model of PCH formation based on the interplay between HP1-based phase separation and chromatin polymer mechanics.
Asunto(s)
Homólogo de la Proteína Chromobox 5 , Heterocromatina , Animales , Heterocromatina/genética , Cinética , Proteínas Cromosómicas no Histona/metabolismo , Cromatina/genética , Drosophila/genética , TermodinámicaRESUMEN
Chirality is ubiquitous in nature across all length scales, with major implications spanning fields from biology, chemistry and physics to materials science. How chirality propagates from nanoscale building blocks to meso- and macroscopic helical structures remains an open issue. Here, working with a canonical system of filamentous viruses, we demonstrate that their self-assembly into chiral liquid crystal phases quantitatively results from the interplay between two main mechanisms of chirality transfer: electrostatic interactions from the helical charge patterns on the virus surface, and fluctuation-based helical deformations leading to viral backbone helicity. Our experimental and theoretical approach provides a comprehensive framework for deciphering how chirality is hierarchically and quantitatively propagated across spatial scales. Our work highlights the ways in which supramolecular helicity may arise from subtle chiral contributions of opposite handedness that act either cooperatively or competitively, thus accounting for the multiplicity of chiral behaviours observed for nearly identical molecular systems.
RESUMEN
We detail the application of bounding volume hierarchies to accelerate second-virial evaluations for arbitrary complex particles interacting through hard and soft finite-range potentials. This procedure, based on the construction of neighbour lists through the combined use of recursive atom-decomposition techniques and binary overlap search schemes, is shown to scale sub-logarithmically with particle resolution in the case of molecular systems with high aspect ratios. Its implementation within an efficient numerical and theoretical framework based on classical density functional theory enables us to investigate the cholesteric self-assembly of a wide range of experimentally relevant particle models. We illustrate the method through the determination of the cholesteric behavior of hard, structurally resolved twisted cuboids, and report quantitative evidence of the long-predicted phase handedness inversion with increasing particle thread angles near the phenomenological threshold value of 45°. Our results further highlight the complex relationship between microscopic structure and helical twisting power in such model systems, which may be attributed to subtle geometric variations of their chiral excluded-volume manifold.
RESUMEN
Recent experimental observations suggest a strong coupling between the 3D nuclear chromosome organization and epigenomics. However, the mechanistic and functional bases of such interplay remain elusive. In this review, we describe how biophysical modeling has been instrumental in characterizing how genome folding may impact the formation of epigenomic domains and, conversely, how epigenomic marks may affect chromosome conformation. Finally, we discuss how this mutual feedback loop between chromatin organization and epigenome regulation, via the formation of physicochemical nanoreactors, may represent a key functional role of 3D compartmentalization in the assembly and maintenance of stable - but yet plastic - epigenomic landscapes.
Asunto(s)
Cromatina , Epigenómica , Cromatina/genética , Genoma/genética , Cromosomas/genética , EpigenomaRESUMEN
Spermiogenesis is a radical process of differentiation whereby sperm cells acquire a compact and specialized morphology to cope with the constraints of sexual reproduction while preserving their main cargo, an intact copy of the paternal genome. In animals, this often involves the replacement of most histones by sperm-specific nuclear basic proteins (SNBPs). Yet, how the SNBP-structured genome achieves compaction and accommodates shaping remain largely unknown. Here, we exploit confocal, electron and super-resolution microscopy, coupled with polymer modeling to identify the higher-order architecture of sperm chromatin in the needle-shaped nucleus of the emerging model cricket Gryllus bimaculatus. Accompanying spermatid differentiation, the SNBP-based genome is strikingly reorganized as ~25nm-thick fibers orderly coiled along the elongated nucleus axis. This chromatin spool is further found to achieve large-scale helical twisting in the final stages of spermiogenesis, favoring its ultracompaction. We reveal that these dramatic transitions may be recapitulated by a surprisingly simple biophysical principle based on a nucleated rigidification of chromatin linked to the histone-to-SNBP transition within a confined nuclear space. Our work highlights a unique, liquid crystal-like mode of higher-order genome organization in ultracompact cricket sperm, and establishes a multidisciplinary methodological framework to explore the diversity of non-canonical modes of DNA organization.
Asunto(s)
Gryllidae , Animales , Masculino , Gryllidae/genética , Semen/metabolismo , Cromatina/genética , Cromatina/metabolismo , Espermatogénesis/genética , Histonas/metabolismo , Espermatozoides/metabolismoRESUMEN
Lyotropic cholesteric liquid crystal phases are ubiquitously observed in biological and synthetic polymer solutions, characterized by a complex interplay between thermal fluctuations and entropic and enthalpic forces. The elucidation of the link between microscopic features and macroscopic chiral structure, and of the relative roles of these competing contributions on phase organization, remains a topical issue. Here, we provide theoretical evidence of a previously unidentified mechanism of chirality amplification in lyotropic liquid crystals, whereby phase chirality is governed by fluctuation-stabilized helical deformations in the conformations of their constituent molecules. Our results compare favorably to recent experimental studies of DNA origami assemblies and demonstrate the influence of intramolecular mechanics on chiral supramolecular order, with potential implications for a broad class of experimentally relevant colloidal systems.
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Cristales Líquidos , ADN/química , Cristales Líquidos/química , Conformación Molecular , Polímeros , TermodinámicaRESUMEN
To study the elastic properties of rodlike DNA nanostructures, we perform long simulations of these structures using the oxDNA coarse-grained model. By analyzing the fluctuations in these trajectories, we obtain estimates of the bend and twist persistence lengths and the underlying bend and twist elastic moduli and couplings between them. Only on length scales beyond those associated with the spacings between the interhelix crossovers do the bending fluctuations behave like those of a wormlike chain. The obtained bending persistence lengths are much larger than that for double-stranded DNA and increase nonlinearly with the number of helices, whereas the twist moduli increase approximately linearly. To within the numerical error in our data, the twist-bend coupling constants are of order zero. That the bending persistence lengths that we obtain are generally somewhat higher than in experiment probably reflects both that the simulated origamis have no assembly defects and that the oxDNA extensional modulus for double-stranded DNA is too large.