Regulation of chromatin microphase separation by binding of protein complexes

Abstract

We show evidence of the association of RNA polymerase II (RNAP) with chromatin in a core-shell organization, reminiscent of microphase separation where the cores comprise dense chromatin and the shell, RNAP and chromatin with low density. These observations motivate our physical model for the regulation of core-shell chromatin organization. Here, we model chromatin as a multiblock copolymer, comprising active and inactive regions (blocks) that are both in poor solvent and tend to be condensed in the absence of binding proteins. However, we show that the solvent quality for the active regions of chromatin can be regulated by the binding of protein complexes (e.g., RNAP and transcription factors). Using the theory of polymer brushes, we find that such binding leads to swelling of the active chromatin regions which in turn modifies the spatial organization of the inactive regions. In addition, we use simulations to study spherical chromatin micelles, whose cores comprise inactive regions and shells comprise active regions and bound protein complexes. In spherical micelles the swelling increases the number of inactive cores and controls their size. Thus, genetic modifications affecting the binding strength of chromatin-binding protein complexes may modulate the solvent quality experienced by chromatin and regulate the physical organization of the genome.

Role of protein-protein interactions on model chromatin organization

“…Despite insights from Hi-C maps and simple polymer models, the role of binding protein-chromatin interactions in organizing chromatin hetero domains remains understudied. In the context of binding protein-chromatin interactions, it is noteworthy to highlight the recent investigation conducted by Adame-Arana and colleagues 24 . They explored the microphase separation of chromatin in the presence of a binding protein that binds reversibly to the active region of the chromatin.…”

“…Loop-extrusion models effectively explain TAD formation 13–18 . In contrast, copolymer models have been employed to explain the formation of chromatin compartments and the promoter-enhancer interactions 8,19–24 . Block copolymers, comprising of two different monomer subchains, exhibit a layered organization in a poor solvent, a process known as microphase separation 25–29 or micelle formation 30 .…”