Disruption of polyhomeotic polymerization decreases nucleosome occupancy and alters genome accessibility

Chromatin attains its three-dimensional (3D) conformation establishing contacts between different noncontiguous regions. Sterile Alpha Motif (SAM)-mediated polymerization of the poly-homeotic (PH) protein regulates subnuclear clustering of Poly comb Repressive Complex 1 (PRC1) and chromatin topology. The mutations that perturb the ability of the PH to polymerize, disrupt long-range chromatin contacts, alter Hox gene expression, and lead to developmental defects. To understand the underlying mechanism, we combined the experiments and theory to in-vestigate the effect of this SAM domain mutation on nucleosome occupancy and accessibility on a genome wide scale. Our data show that disruption of PH polymerization because of SAM do-main mutation decreases nucleosome occupancy and alters ac-cessibility. Polymer simulations investigating the interplay between distant chromatin contacts and nucleosome occupancy, both which are regulated by PH polymerization, suggest that nucle-osome density increases when contacts between different re-gions of chromatin are established. Taken together, it appears that SAM domain-mediated PH polymerization biomechanically regulates the organization of chromatin at multiple scales from nucleosomes to chromosomes and we suggest that higher order organization can have a top-down causation effect on nucleo-some occupancy.

Automated summary

Chromatin conformation is regulated by SAM domain-mediated polymerization of PH protein, which controls subnuclear clustering of PRC1 and chromatin topology. Mutations affecting PH polymerization disrupt long-range chromatin contacts, alter Hox gene expression, and result in developmental defects. Our study demonstrates that SAM domain mutations decrease nucleosome occupancy and alter accessibility, and simulations reveal that PH polymerization regulates the interplay between chromatin contacts and nucleosome occupancy. We propose that SAM domain-mediated PH polymerization biomechanically regulates chromatin organization across multiple scales and can influence nucleosome occupancy in a top-down manner.