BPS2026 – Molecular mechanisms in packaging and organizing chromatin as condensates

The genome must be folded and organized inside the nucleus so that some regions are accessible while others remain silent. Establishing these different kinds of chromatin domains is key in maintaining cell’s state and to avoid dysregulated expression of genes during disease. The nucleosomes that compact and help fit DNA into cells are highly multivalent; intrinsically disordered and charged histone tails emanate from nucleosomes, which are repeated millions of times across the genome. Previously, I reported how these associative features provide chromatin with a capacity to phase separate and package DNA in condensates to cell-like levels. These condensates are regulate-able in manners suggestive of its utility for genome organization. Here, we report our investigations into the molecular mechanisms that drive condensation of chromatin. Using quantitative imaging, we can measure interaction energies on molecules that undergo phase separation, building a mechanistic framework surrounding their associations. With this approach, we have found that histone tails engage in complex collaborations to condense chromatin; from shorter-to-longer lengths, interaction surfaces promote or inhibit self-association, which may provide avenues for regulation of this activity in cells. Further, we outline how engagement by nuclear factors impacts the microenvironment of condensates and what regions in the genome retain this activity. Altogether, these results advance a biophysical perspective for genome organization—how self-assembly and phase transitions can specify differently packaged and functioning mesoscale chromatin domains.