How Do Nucleosomes Bundle DNA into Chromatin?

Abstract

The binding of histones and the formation of nucleosomes play major roles in bundling DNA into chromatin in eukaryotic cells. This process not only facilitates the packaging of DNA in the cell nucleus but also influences the communication between distant genomic sites, such as enhancers and promoters found at the ends of protein-mediated loops. The details of chromatin organization, however, remain unclear. In particular, the effects of nucleosome positioning (i.e., the sequential locations of nucleosomes along DNA) on chromatin architecture are still poorly understood. With a view toward understanding the interplay between nucleosomes and DNA in chromatin, we have developed a mesoscale model of nucleosome-decorated DNA at a resolution of a single base pair. We use Monte Carlo numerical strategies to unravel how nucleosomes shape DNA into chromatin and we validate our model by successfully reproducing various experimental measurements. With the help of a cloud computing approach we have been able to perform simulations for a wide range of nucleosome positionings, that is, for a wide range of DNA linker lengths. Our results show a broad variety of chromatin organization. This structural diversity, which extends beyond the conventional solenoid and zigzag models of chromatin, comes along with very different physical and mechanical properties, such as apparent bending and twisting stiffnesses and degrees of compaction. We have also studied how fluctuations in nucleosome positioning can affect chromatin. We have found that minor changes of the order of a few base pairs in the locations of nucleosomes along DNA can greatly alter the local and global properties of chromatin. Our work shows that the synergy between DNA and nucleosomes in chromatin gives rise to a highly versatile biomolecule, which is able to accommodate tight packing while maintaining the accessibility necessary for specific expression.