Abstract
The spatial organization of nucleosomes in 30-nm fibers remains unknown in detail. To tackle this problem, we analyzed all stereochemically possible configurations of two-start chromatin fibers with DNA linkers L = 10–70 bp (nucleosome repeat length NRL = 157–217 bp). In our model, the energy of a fiber is a sum of the elastic energy of the linker DNA, steric repulsion, electrostatics, and the H4 tail-acidic patch interaction between two stacked nucleosomes. We found two families of energetically feasible conformations of the fibers—one observed earlier, and the other novel. The fibers from the two families are characterized by different DNA linking numbers—that is, they are topologically different. Remarkably, the optimal geometry of a fiber and its topology depend on the linker length: the fibers with linkers L = 10n and 10n + 5 bp have DNA linking numbers per nucleosome ΔLk ≈ −1.5 and −1.0, respectively. In other words, the level of DNA supercoiling is directly related to the length of the inter-nucleosome linker in the chromatin fiber (and therefore, to NRL). We hypothesize that this topological polymorphism of chromatin fibers may play a role in the process of transcription, which is known to generate different levels of DNA supercoiling upstream and downstream from RNA polymerase. A genome-wide analysis of the NRL distribution in active and silent yeast genes yielded results consistent with this assumption.
Highlights
Eukaryotic DNA is spatially organized in a hierarchical manner, the first level being the chain of nucleosomes connected by DNA linkers (“beads on a string”)
Our computations demonstrate significant variability of two-start chromatin fibers (Figure 3), which is the result of interplay between the linker DNA twisting and the inclination of nucleosomal disks (Figure 1)
Note the nearly two-fold increase in diameter of fibers accompanying a linker increase from 10–15 to 60–65 bp. This trend is to be expected because the linker length dictates the diameter
Summary
Eukaryotic DNA is spatially organized in a hierarchical manner, the first level being the chain of nucleosomes connected by DNA linkers (“beads on a string”). During the past decade there has been a significant progress in the structural studies of chromatin, starting with the seminal studies of Richmond and co-authors, who first observed the two-start fibers (Dorigo et al [6] and Schalch et al [7]) Their results, together with the high-resolution Cryo-EM data obtained by Song et al [8] strongly support the two-start organization of chromatin fibers for relatively short linkers L = 20, 30 and 40 bp. The electron microscopy (EM) images presented by Rhodes and co-authors [9,10] suggest that for L = 50 bp and longer, the one-start solenoid (or interdigitaded structure) is more stable, especially in the presence of linker histones All these structures were obtained for arrays of strongly positioned “601” nucleosomes [11], with the nucleosome repeat length (NRL) varying from 167 to 237 bp in increments of 10 bp. The structural data mentioned above correspond to linker lengths with occurrences in vivo that are relatively small
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