Sequence-dependent nucleosome sliding in rotation-coupled and uncoupled modes revealed by molecular simulations

Abstract

While nucleosome positioning on eukaryotic genome play important roles for genetic regulation, molecular mechanisms of nucleosome positioning and sliding along DNA are not well understood. Here we investigated thermally-activated spontaneous nucleosome sliding mechanisms developing and applying a coarse-grained molecular simulation method that incorporates both long-range electrostatic and short-range hydrogen-bond interactions between histone octamer and DNA. The simulations revealed two distinct sliding modes depending on the nucleosomal DNA sequence. A uniform DNA sequence showed frequent sliding with one base pair step in a rotation-coupled manner, akin to screw-like motions. On the contrary, a strong positioning sequence, the so-called 601 sequence, exhibits rare, abrupt transitions of five and ten base pair steps without rotation. Moreover, we evaluated the importance of hydrogen bond interactions on the sliding mode, finding that strong and weak bonds favor respectively the rotation-coupled and -uncoupled sliding movements. Author summaryNucleosomes are fundamental units of chromatin folding consisting of double-stranded DNA wrapped ~1.7 times around a histone octamer. By densely populating the eukaryotic genome, nucleosomes enable efficient genome compaction inside the cellular nucleus. However, the portion of DNA occupied by a nucleosome can hardly be accessed by other DNA-binding proteins, obstructing fundamental cellular processes such as DNA replication and transcription. DNA compaction and access by other proteins can simultaneously be achieved via the dynamical repositioning of nucleosomes, which can slide along the DNA sequence. In this study, we developed and used coarse-grained molecular dynamics simulations to reveal the molecular details of nucleosome sliding. We find that the sliding mode is highly dependent on the underlying DNA sequence. Specifically, a sequence with a strong nucleosome positioning signal slides via large jumps by five and ten base pairs, preserving the optimal DNA bending profile. On the other hand, uniform sequences without the positioning signal slide via a screw-like motion of DNA, one base pair at the time. These results show that sequence has a large effect not only on the formation of nucleosomes, but also on the kinetics of repositioning.

Nucleosomal DNA dynamics mediate Oct4 pioneer factor binding

“…We found significant differences between the dynamics of the 3 nucleosomes, the nucleosome with most TF binding sites showing the largest amplitude of breathing and twisting motions. This is in agreement with previous studies that revealed the more dynamic nature of natural nucleosomes 13,22,28 .…”

“…Despite the lack of full sampling convergence, we observed a good overlap between independent simulations for nucleosome breathing (Fig 3) and we achieved a wider conformational sampling by combining independent simulations of the same species into ensembles. This enabled us to study both breathing and twisting motions in the nucleosomes and to conclude about the sequence dependence of these motions at a level of detail not feasible in coarse grained simulations, which were previously used to study nucleosome dependent dynamics 22,28 . The atomic resolution provides the means to study the determinant modulators of nucleosome dynamics such the motion of histone tails or the role of anchoring histone residues 15 .…”

“…Nevertheless, all these previous atomic resolution MD simulations 19 were started from the most complete crystal structure of the nucleosome 20 , using a palindromic DNA sequence derived from human α-satellite DNA. Interestingly, coarse-grained MD simulations, in which several non-hydrogen atoms are grouped in beads have been performed with different DNA sequences [21][22][23] . Many of these studies used the Widom 601 artificial sequence 22,24 , an artificial sequence selected for its stability 25 that is present in many crystal structures of the nucleosome 26,27 .…”

“…Interestingly, coarse-grained MD simulations, in which several non-hydrogen atoms are grouped in beads have been performed with different DNA sequences [21][22][23] . Many of these studies used the Widom 601 artificial sequence 22,24 , an artificial sequence selected for its stability 25 that is present in many crystal structures of the nucleosome 26,27 . Due to the reduced representation, the computational cost of these simulations is much lower.…”

“…Therefore, questions that require longer and a higher number of simulations can be addressed. As a result, models of sequence-specific nucleosome dynamics, revealing the role of the sequence in nucleosome breathing and unwrapping 22,28 , or protein-mediated remodeling 29 have been established. However, the descriptions obtained from coarse grained simulations is limited because important details regarding the interactions that modulate nucleosome dynamics are missing.…”