Genetic information that dictates cell fate and function is encoded in DNA. In eukaryotic cells, DNA is packaged into chromatin, a highly compact and intricate structure within the nucleus. Chromatin compaction is a key regulator of gene expression; however, the mechanisms underlying this process are not yet fully understood. A recently emerging paradigm proposes that chromatin and its associated proteins can undergo liquid-liquid phase separation (LLPS), both in vitro and in vivo. Through the formation of condensates, DNA regions can be spatially segregated, thereby selectively exposing specific genes to transcriptional machinery and regulatory proteins. To investigate the structure and dynamics of chromatin arrays within condensates, we combine cryo-electron tomography (cryo-ET) with our multiscale chromatin model. Our model enhances the resolution of cryo-ET, resolving chromatin droplets at single-amino acid and base-pair resolution, enabling us to characterize individual nucleosomes. By analyzing condensates formed with different linker DNA lengths, our simulations demonstrate how the mechanical properties of DNA govern the structural and dynamical behavior of chromatin arrays inside droplets. Furthermore, we reveal how distinct interaction patterns between histone tails and DNA stabilize the diverse architectures that chromatin adopts within condensates. Together, our work highlights how integrating cryo-ET with multiscale modeling provides a powerful framework for deciphering the organization and dynamics of biomolecules within condensates at sub-molecular resolution with physicochemical accuracy.
Martin et al. (Sun,) studied this question.