Nonspecific steric hindrance of protein particles by lamina–associated domains

Abstract Genomic organization within the nucleus is crucial for gene regulation and cell health, as disruptions in this organization are linked to genetic disorders and cancers. Recent studies suggest that molecular-scale organization of chromatin near the nuclear periphery (lamina-associated domains, LADs) affects gene regulation, providing transciptional supression, but the biophysical mechanisms of supression behind remain unclear. LADs are large heterochromatic regions near the nuclear lamina, where transcriptional factors and RNA polymerase are scarce, implying a nonspecific filtering property. Here, we investigate the steric filtering capabilities of LADs by performing coarse-grained polymer simulations. Our results show that LAD thickness can be affected by the interaction between chromatin and nuclear periphery as well as chromatin self-compaction. Regardless, the LAD layer acts as a size-selective steric partitioning environment for protein particles limiting their access to nuclear periphery. Notably, increasing bulk protein levels enhances protein access linearly. These results align with experimental observations and suggest that LADs could control the presence of transcription machinery on the periphery of the nucleus, providing a polymer-physical mechanism for gene regulation in nuclei. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵† ossariyer{at}pirireis.edu.tr