As the basic packaging units of eukaryotic genomes, nucleosomes provide both a rich medium for accumulation of epigenetic marks and a physical barrier that restricts access to DNA. These two nucleosomal features – presenting epigenetic signatures and blocking DNA access – are integrated by a diverse group of protein machines called chromatin remodelers. Chromatin remodelers can read epigenetic marks through auxiliary domains or associated subunits and can assemble, reposition, and disassemble nucleosomes in an ATP-dependent fashion [1
]. The unifying feature of chromatin remodelers is a helicase-like ATPase motor required for nucleosome reorganization. A major challenge in the remodeling field is to understand how this ATPase motor engages with and manipulates nucleosomal DNA to effectively deposit, remove, and slide nucleosomes along DNA.
An early idea for how the central histone core might be shifted along the DNA is known as the twist diffusion model () [3
]. This model suggests that single base pairs can be transferred between linker DNA and the DNA wrapped around the histone core, such that segments of nucleosomal DNA twist or untwist to accommodate the loss or gain of one or more base pairs. Although such a loss or gain would generate a twist defect in a segment of nucleosomal DNA, the model predicts that a small twist defect could be tolerated by the nucleosome without disrupting histone-DNA contacts. If a twist defect from one or more base pairs were propagated all the way around the nucleosome from one DNA segment to the next, so-called twist diffusion, the histone octamer would effectively shift along the DNA by the size of the distortion. This model has been strengthened by the discovery of structural variability around the histone core, where certain regions of the nucleosome can support a gain or loss of one base pair [6
]. However, due to the helical nature of DNA, shifting DNA past the histone core one base pair at a time would necessitate rotation of the DNA by ~35° with each base pair step, which would alter the rotational phasing of the DNA on the histone core. Notably, ATP-dependent nucleosome sliding is not inhibited by physical barriers such as DNA hairpins and biotin crosslinks that should prevent rotation of the DNA duplex during sliding [10
]. In addition, chromatin remodelers have been reported to slide nucleosomes in increments of approximately 10 base pair steps, maintaining the rotational phasing of nucleosomal DNA [12
””]. Thus, while twist diffusion remains an attractive mechanism for shifting nucleosomes along DNA in response to thermal fluctuations [5
], chromatin remodelers likely utilize a different mechanism for ATP-dependent sliding of nucleosomes.
FIGURE 1 Two current models for nucleosome sliding. (a) The twist diffusion model [3–5]. In this model, a segment of DNA at the entry/exit site of the nucleosome releases or absorbs a single base pair from the linker DNA. In the figure, an additional base (more ...)
A distinct but related model for nucleosome sliding is known as the loop or bulge propagation model () [13
]. Similar to twist diffusion, the loop/bulge propagation model suggests that DNA from one linker transiently shifts onto the nucleosome, creating a loop or bulge of DNA that rapidly diffuses around the histone core to emerge on the other side. An important difference from twist diffusion is the idea that DNA is pushed onto the nucleosome in larger segments, thus locally disrupting one or more contacts with the histone core. The loss of histone-DNA contacts makes a DNA loop more energetically expensive than a twist defect, but unlike twist diffusion, loop propagation should allow DNA to maintain rotational phasing on the histone core [16
Biochemical and single molecule experiments have brought into question several key assumptions that originally made loop propagation attractive, and two variations on the loop propagation model (discussed below) have emerged to address these new findings. The recent experimental results also allow for an alternative model for nucleosome sliding, originally dismissed on structural grounds, where the DNA slips past the histone core in a concerted motion. Such a shift would be equivalent to a rotation or swiveling of the histone core with respect to the outer wrapping of DNA, and effectively move the histone core along DNA without a change in rotational phasing.