Cooperative Contributions of Nucleosome Components on the Higher-Order Structure of Six-Nucleosome Arrays

The higher-order organization of eukaryotic chromatin is crucial for the regulation and control of DNA accessibility, thereby modulating essential processes such as transcription, replication, DNA repair, and chromosome segregation. As the fundamental unit of chromatin, nucleosome array conformations are modulated by multiple factors like histone tails, linker histone H1, and histone modifications, yet the physicochemical mechanisms of such regulations remain incompletely understood. Understanding the principles governing nucleosome array conformation not only reveals core epigenetic mechanisms but also provides critical insights for therapeutic targeting in epigenetic diseases. Here, we systematically investigated the regulatory roles of core histone tails, linker histone H1, and histone acetylation on nucleosome array folding using coarse-grained molecular dynamics simulations. It was found that histone tails stabilize internucleosomal contacts, while H1 promotes array compaction and twisting by constraining linker DNA. Histone acetylation attenuates H1-imposed constraints at the DNA entry-exit sites through long-range effects and suppresses H1-induced twisting, with acetylation of H3/H4/H2B having the most pronounced effects. Additionally, acetylation significantly increases the solvent-accessible surface area of nucleosomal and linker DNA, indicating enhanced DNA exposure. Together, these findings elucidate the structural basis of higher-order chromatin organization and suggest a mechanistic link between chromatin architecture, DNA accessibility, and thus transcription regulation.