From 1D sequence to 3D chromatin dynamics and cellular functions: a phase separation perspective

The high-order chromatin structure plays a non-negligible role in gene regulation. However, the mechanism, especially the sequence dependence for the formation of varied chromatin structures in different cells remains to be elucidated. As the nucleotide distributions in human and mouse genomes are highly uneven, we identified CGI (CpG island) forest and prairie genomic domains based on CGI densities of a species, dividing the genome into two sequentially, epigenetically, and transcriptionally distinct regions. These two megabase-sized domains also spatially segregate to different extents in different cell types. Forests and prairies show enhanced segregation from each other in development, differentiation, and senescence, meanwhile the multi-scale forest-prairie spatial intermingling is cell-type specific and increases in differentiation, helping to define cell identity. We propose that the phase separation of the 1D mosaic sequence in 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. The mosaicity in genome of different species in terms of forests and prairies could relate to observations in their biological processes like development and aging. In this way, we provide a bottoms-up theory to explain the chromatin structural and epigenetic changes in different processes.