Nucleosome positioning and composition modulate in silico chromatin flexibility

Abstract

The dynamic organization of chromatin plays an essential role in the regulation of gene expression and in other fundamental cellular processes. The underlying physical basis of these activities lies in the sequential positioning, chemical composition, and intermolecular interactions of the nucleosomes—the familiar assemblies of ~ 150 DNA base pairs and eight histone proteins—found on chromatin fibers. Here we introduce a mesoscale model of short nucleosomal arrays and a computational framework that make it possible to incorporate detailed structural features of DNA and histones in simulations of short chromatin constructs. We explore the effects of nucleosome positioning and the presence or absence of cationic N-terminal histone tails on the ‘local’ inter-nucleosomal interactions and the global deformations of the simulated chains. The correspondence between the predicted and observed effects of nucleosome composition and numbers on the long-range communication between the ends of designed nucleosome arrays lends credence to the model and to the molecular insights gleaned from the simulated structures. We also extract effective nucleosome-nucleosome potentials from the simulations and implement the potentials in a larger-scale computational treatment of regularly repeating chromatin fibers. Our results reveal a remarkable effect of nucleosome spacing on chromatin flexibility, with small changes in DNA linker length significantly altering the interactions of nucleosomes and the dimensions of the fiber as a whole. In addition, we find that these changes in nucleosome positioning influence the statistical properties of long chromatin constructs. That is, simulated chromatin fibers with the same number of nucleosomes exhibit polymeric behaviors ranging from Gaussian to worm-like, depending upon nucleosome spacing. These findings suggest that the physical and mechanical properties of chromatin can span a wide range of behaviors, depending on nucleosome positioning, and that care must be taken in the choice of models used to interpret the experimental properties of long chromatin fibers.

Contributions of Sequence to the Higher-Order Structures of DNA

“…However, until we obtain a greater collection of experimentally determined structures of nucleosome arrays, our knowledge about chromatin deformability and the associated interactions of nucleosomes must rely upon computer-simulated data. The correspondence between prediction and observation revealed in these studies, such as those that take successful account of communication between proteins at the ends of nucleosome arrays (15)(16)(17), lends credence to the computations and to the molecular insights gleaned from the simulations. On the other hand, the current mesoscale models of chromatin may not necessarily account for new observations and thus will require continued testing and refinement against all available experimental data.…”

“…The available high-resolution structures provide similarly sketchy hints as to how pairs of nucleosomes may associate along chromatin fibers. Consideration of the close crystallographic contacts on the exposed upper and lower faces of the wedge-shaped histone core (26,48,49) has proven useful in the development of models that account successfully for low-resolution structures and properties of chromatin (17,18).…”

“…The available high-resolution structures provide similarly sketchy hints as to how pairs of nucleosomes may associate along chromatin fibers. Consideration of the close crystallographic contacts on the exposed upper and lower faces of the wedge-shaped histone core (26,48,49) has proven useful in the development of models that account successfully for low-resolution structures and properties of chromatin (17,18).The influence of sequence on the spatial properties of unconstrained, bare, linear DNA chains is more subtle. Consideration of the sequence-dependent structure and deformability of individual basepair steps shifts and narrows the computed distribution of end-to-end distances of a 147-bp stretch of the 601 nucleosome-positioning sequence compared with that of a piece of ideal DNA of the same length (Fig.…”

“…The approximate representation of local structure and dynamics (at levels ranging from individual to tens of basepairs) has proven useful for interpreting the configurational properties of short proteinmediated DNA loops (10-13) and well-defined chromatin constructs (14)(15)(16)(17)(18), including the long-range communication between different parts of model oligonucleosome chains and the spatial pathways captured with microscopic techniques. Mesoscale studies tend to ignore the influences of DNA sequence other than those associated with certain well-known nucleotide repeating patterns, such as the natural curvature of so-called A-tracts.…”

“…The novel shape and charge sites, combined with mobile point charges on the histone tails, allow for closer packing of nucleosomes than would be possible with a conventional cylindrical depiction (59) of the core particle. The treatment of histone charges in terms of static points representative of the sites of cationic and anionic amino acids in the histone core structure and mobile points on the exposed histone tails (17), although more coarse-grained than some other approaches (58), gives rise to an attractive term when the histone tails of one nucleosome come into contact with the acidic patch on another. The looping propensities based on this model mirror the enhancement in long-range communication between regulatory proteins found on nucleosome arrays and the variations in communication levels with the numbers, composition, and spacing of nucleosomes (15).…”