Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA.
TL;DR: The molecular mechanism of active nucleosome sliding is investigated by means of molecular dynamics simulations of the Snf2 remodeler translocase in complex with a nucleosomes to offer a detailed mechanistic picture of remodeling important for the complete understanding of these key biological processes.
Abstract: ATP-dependent chromatin remodelers are molecular machines that control genome organization by repositioning, ejecting, or editing nucleosomes, activities that confer them essential regulatory roles on gene expression and DNA replication. Here, we investigate the molecular mechanism of active nucleosome sliding by means of molecular dynamics simulations of the Snf2 remodeler translocase in complex with a nucleosome. During its inchworm motion driven by ATP consumption, the translocase overwrites the original nucleosome energy landscape via steric and electrostatic interactions to induce sliding of nucleosomal DNA unidirectionally. The sliding is initiated at the remodeler binding location via the generation of a pair of twist defects, which then spontaneously propagate to complete sliding throughout the entire nucleosome. We also reveal how remodeler mutations and DNA sequence control active nucleosome repositioning, explaining several past experimental observations. These results offer a detailed mechanistic picture of remodeling important for the complete understanding of these key biological processes.
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TL;DR: In this article, a nucleosome-DNA interaction model was proposed to predict the genome-wide organization of nucleosomes, and it was shown that genomes encode an intrinsic nucleosomal organization and that this intrinsic organization can explain ∼50% of the in-vivo positions.
Abstract: Eukaryotic genomes are packaged into nucleosome particles that occlude the DNA from interacting with most DNA binding proteins. Nucleosomes have higher affinity for particular DNA sequences, reflecting the ability of the sequence to bend sharply, as required by the nucleosome structure. However, it is not known whether these sequence preferences have a significant influence on nucleosome position in vivo, and thus regulate the access of other proteins to DNA. Here we isolated nucleosome-bound sequences at high resolution from yeast and used these sequences in a new computational approach to construct and validate experimentally a nucleosome–DNA interaction model, and to predict the genome-wide organization of nucleosomes. Our results demonstrate that genomes encode an intrinsic nucleosome organization and that this intrinsic organization can explain ∼50% of the in vivo nucleosome positions. This nucleosome positioning code may facilitate specific chromosome functions including transcription factor binding, transcription initiation, and even remodelling of the nucleosomes themselves.
1,399 citations
TL;DR: It is proposed that DNA buffering ensures nucleosome stability during ATP-dependent remodelling, and provides a means for communication between remodellers acting on opposite sides of the nucleosomes in real-time.
Abstract: ATP-dependent chromatin remodelling enzymes (remodellers) regulate DNA accessibility in eukaryotic genomes. Many remodellers reposition (slide) nucleosomes, however, how DNA is propagated around the histone octamer during this process is unclear. Here we examine the real-time coordination of remodeller-induced DNA movements on both sides of the nucleosome using three-colour single-molecule FRET. During sliding by Chd1 and SNF2h remodellers, DNA is shifted discontinuously, with movement of entry-side DNA preceding that of exit-side DNA. The temporal delay between these movements implies a single rate-limiting step dependent on ATP binding and transient absorption or buffering of at least one base pair. High-resolution cross-linking experiments show that sliding can be achieved by buffering as few as 3 bp between entry and exit sides of the nucleosome. We propose that DNA buffering ensures nucleosome stability during ATP-dependent remodelling, and provides a means for communication between remodellers acting on opposite sides of the nucleosome. Chromatin remodelling enzymes (remodellers) regulate DNA accessibility of eukaryotic genomes, which rely in large part on an ability to reposition nucleosomes. Here the authors use three-colour single-molecule FRET to simultaneously monitor remodeller-induced DNA movements on both sides of the nucleosome in real-time.
68 citations
TL;DR: In this article, the effects of internal active forces and torques on a 3D droplet of cholesteric liquid crystal (CLC) embedded in an isotropic liquid were investigated.
Abstract: Chirality is a recurrent theme in the study of biological systems, in which active processes are driven by the internal conversion of chemical energy into work. Bacterial flagella, actomyosin filaments, and microtubule bundles are active systems that are also intrinsically chiral. Despite some exploratory attempt to capture the relations between chirality and motility, many features of intrinsically chiral systems still need to be explored and explained. To address this gap in knowledge, here we study the effects of internal active forces and torques on a 3-dimensional (3D) droplet of cholesteric liquid crystal (CLC) embedded in an isotropic liquid. We consider tangential anchoring of the liquid crystal director at the droplet surface. Contrary to what happens in nematics, where moderate extensile activity leads to droplet rotation, cholesteric active droplets exhibit more complex and variegated behaviors. We find that extensile force dipole activity stabilizes complex defect configurations, in which orbiting dynamics couples to thermodynamic chirality to propel screw-like droplet motion. Instead, dipolar torque activity may either tighten or unwind the cholesteric helix and if tuned, can power rotations with an oscillatory angular velocity of 0 mean.
43 citations
TL;DR: The cryo-electron microscopy structure of Homo sapiens CHD4 engaged with a nucleosome core particle in the presence of the non-hydrolysable ATP analogue AMP-PNP at an overall resolution of 3.1 Å supports the ‘twist defect’ model of chromatin remodeling.
Abstract: Chromatin remodeling plays important roles in gene regulation during development, differentiation and in disease. The chromatin remodeling enzyme CHD4 is a component of the NuRD and ChAHP complexes that are involved in gene repression. Here, we report the cryo-electron microscopy (cryo-EM) structure of Homo sapiens CHD4 engaged with a nucleosome core particle in the presence of the non-hydrolysable ATP analogue AMP-PNP at an overall resolution of 3.1 A. The ATPase motor of CHD4 binds and distorts nucleosomal DNA at superhelical location (SHL) +2, supporting the 'twist defect' model of chromatin remodeling. CHD4 does not induce unwrapping of terminal DNA, in contrast to its homologue Chd1, which functions in gene activation. Our structure also maps CHD4 mutations that are associated with human cancer or the intellectual disability disorder Sifrim-Hitz-Weiss syndrome.
38 citations
Cites background from "Chromatin remodelers couple inchwor..."
...A possible mechanism for coordination could be that twist defects that are introduced by remodeler binding are propagated from the entry SHL 2 into the exit side SHL 2 (Brandani et al., 2018; Brandani and Takada, 2018)....
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TL;DR: In this article, the authors review the progress that has been made in modeling the human genome and conclude with an outlook on the opportunities and challenges in studying chromosome dynamics, and provide insight into the principles of whole-genome organization and enable de novo predictions of chromosome structures from epigenetic modifications.
Abstract: Three-dimensional (3D) organization of the human genome plays an essential role in all DNA-templated processes, including gene transcription, gene regulation, and DNA replication. Computational modeling can be an effective way of building high-resolution genome structures and improving our understanding of these molecular processes. However, it faces significant challenges as the human genome consists of over 6 × 109 base pairs, a system size that exceeds the capacity of traditional modeling approaches. In this perspective, we review the progress that has been made in modeling the human genome. Coarse-grained models parameterized to reproduce experimental data via the maximum entropy optimization algorithm serve as effective means to study genome organization at various length scales. They have provided insight into the principles of whole-genome organization and enabled de novo predictions of chromosome structures from epigenetic modifications. Applications of these models at a near-atomistic resolution further revealed physicochemical interactions that drive the phase separation of disordered proteins and dictate chromatin stability in situ. We conclude with an outlook on the opportunities and challenges in studying chromosome dynamics.
32 citations
References
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TL;DR: The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it.
Abstract: The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it. Both histone/histone and histone/DNA interactions depend on the histone fold domains and additional, well ordered structure elements extending from this motif. Histone amino-terminal tails pass over and between the gyres of the DNA superhelix to contact neighbouring particles. The lack of uniformity between multiple histone/DNA-binding sites causes the DNA to deviate from ideal superhelix geometry.
7,841 citations
TL;DR: In this paper, a set of highest affinity molecules were selected, cloned and sequenced, their affinities (free energies) for histone octamer in nucleosome reconstitution measured, and their ability to position nucleosomes in vitro assessed by native gel electrophoresis.
1,587 citations
TL;DR: In this article, the authors present general considerations and simple models for the operation of isothermal motors at small scales, in asymmetric environments, inspired by recent observations on the behavior of molecular motors in the biological realm, where chemical energy is converted into mechanical energy.
Abstract: The authors present general considerations and simple models for the operation of isothermal motors at small scales, in asymmetric environments. Their work is inspired by recent observations on the behavior of molecular motors in the biological realm, where chemical energy is converted into mechanical energy. A generic Onsager-like description of the linear (close to equilibrium) regime is presented, which exhibits structural differences from the usual Carnot engines. Turning to more explicit models for a single motor, the authors show the importance of the time scales involved and of the spatial dependence of the motor{close_quote}s chemical activity. Considering the situation in which a large collection of such motors operates together. The authors exhibit new features among which are dynamical phase transitions formally similar to paramagnetic-ferromagnetic and liquid-vapor transitions. {copyright} {ital 1997} {ital The American Physical Society}
1,486 citations
TL;DR: If a highly accurate MEP is desired, it is found to be more efficient to descend from the saddle to the minima than to use a chain-of-states method with many images.
Abstract: A comparison of chain-of-states based methods for finding minimum energy pathways (MEPs) is presented. In each method, a set of images along an initial pathway between two local minima is relaxed to find a MEP. We compare the nudged elastic band (NEB), doubly nudged elastic band, string, and simplified string methods, each with a set of commonly used optimizers. Our results show that the NEB and string methods are essentially equivalent and the most efficient methods for finding MEPs when coupled with a suitable optimizer. The most efficient optimizer was found to be a form of the limited-memory Broyden-Fletcher-Goldfarb-Shanno method in which the approximate inverse Hessian is constructed globally for all images along the path. The use of a climbing-image allows for finding the saddle point while representing the MEP with as few images as possible. If a highly accurate MEP is desired, it is found to be more efficient to descend from the saddle to the minima than to use a chain-of-states method with many images. Our results are based on a pairwise Morse potential to model rearrangements of a heptamer island on Pt(111), and plane-wave based density functional theory to model a rollover diffusion mechanism of a Pd tetramer on MgO(100) and dissociative adsorption and diffusion of oxygen on Au(111).
1,409 citations
Journal Article•
TL;DR: In this article, a nucleosome-DNA interaction model was proposed to predict the genome-wide organization of nucleosomes, and it was shown that genomes encode an intrinsic nucleosomal organization and that this intrinsic organization can explain ∼50% of the in-vivo positions.
Abstract: Eukaryotic genomes are packaged into nucleosome particles that occlude the DNA from interacting with most DNA binding proteins. Nucleosomes have higher affinity for particular DNA sequences, reflecting the ability of the sequence to bend sharply, as required by the nucleosome structure. However, it is not known whether these sequence preferences have a significant influence on nucleosome position in vivo, and thus regulate the access of other proteins to DNA. Here we isolated nucleosome-bound sequences at high resolution from yeast and used these sequences in a new computational approach to construct and validate experimentally a nucleosome–DNA interaction model, and to predict the genome-wide organization of nucleosomes. Our results demonstrate that genomes encode an intrinsic nucleosome organization and that this intrinsic organization can explain ∼50% of the in vivo nucleosome positions. This nucleosome positioning code may facilitate specific chromosome functions including transcription factor binding, transcription initiation, and even remodelling of the nucleosomes themselves.
1,399 citations