1d Sequence Based 3d Chromatin Phase Separation: Forces, Processes, And Functions

The high-order chromatin structure plays a non-negligible role in gene regulation. The formation of chromatin structure and its regulatory mechanisms have been studied intensely. To analyze the high-order chromatin structures, both computational and physical models have been developed, including polymer physics models and molecular crowding models. Over the past few years, the phase separation theory has drawn a lot of research interest, and the effect of heterochromatin and transcriptional factors (TFs) on phase separation has attracted much attention. Existing phase separation models for chromatin focus on multivalent molecules or on epigenetic properties and does not adequately explore the dependence of chromatin structure organization and remodeling on DNA sequence. Genomes of a number of species are highly uneven at multiple scales. It can be divided purely based on sequential properties into two sequentially, epigenetically, and transcriptionally distinct regions, namely forest and prairie domains, demonstrating the intrinsic mosaicity in genome. Compared to prairies, forest domains are on average more gene-rich, accessible, transcriptionally active, higher in open-sea methylation level, and are enriched in RNA polymerase II binding sites as well as active histone modifications. Moreover, different structural properties of these two types of sequential domains suggest that sequence may play a role in topologically associated domain (TAD) and compartment formation. The chromatin sequence-structural relationship and functional regulation in different cell types with almost identical sequences are discussed in this review. We try to describe the evolution of chromatin structure in multiple biological processes including early development, differentiation, and senescence in a unified framework. The forest and prairie domains with high and low CGI densities, respectively, show enhanced segregation from each other in development, differentiation, and senescence. Meanwhile the multiscale forest-prairie spatial intermingling is cell-type specific and increases upon differentiation, thereby helping to define cell identity. The consistency between chromatin structure and open-sea methylation level suggests that the latter is a promising indicator of structural segregation, deepening our understanding of epigenetic-structure relation. We further discuss the physical driving forces of phase separation as well as their biological implications. The phase separation of the uneven 1D sequence in 3D space serves as a potential driving force, and together with cell type specific epigenetic marks and transcription factors shapes the chromatin structure in different cell types. Transcriptional complex along with dynamic TFs and epigenetic marks may account for local structure formation and separation, regulating chromatin structure at a smaller spatial-temporal scale based on their sequential environment. Finally, role of physical factors like temperature and sequence unevenness in affecting chromatin structure have also been discussed.