High Throughput Simulations Reveal how Sequence and Methylation Control DNA Looping and Self-Association

Abstract

The three-dimensional organization of chromosomes spans multiple scales, from looping of DNA around a histone particle in a nucleosome to folding of multiple nucleosomes into complex structures. Such organization is known to change during the cell cycle, differ from tissue to tissue and from diseased to healthy cells. Strikingly, such large-scale organization is orchestrated by atom-scale modifications to DNA and histone proteins known as epigenetic markers. By combining high-throughput molecular dynamics simulations with single-molecule experiments, we have uncovered some of the microscopic mechanisms that govern DNA looping and nucleosome-nucleosome association. At a single DNA loop level, we found the nucleotide sequence of DNA and its CpG methylation to uniquely determine which face of the DNA loop points inward, toward the histone core of a nucleosome, or outward, toward the DNA reader machinery. The energetics of such DNA loop reorientation is found to correlate with the experimentally determined sequence dependence of DNA looping. At a multi-nucleosome level, we found that the DNA's AT content and/or epigenetic modifications on either DNA or histone tails can govern association of nucleosomes into clusters. Overall, our findings suggest that intrinsic properties of DNA may play a considerable role in large-scale organization of chromosomes.