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

Abstract

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.

Progressive domain segregation in early embryonic development and underlying correlation to genetic and epigenetic changes

“…It is well known that the entire genome can be partitioned into two spatial compartments (A and B) 20 . It was also found that forest domains reside mainly in compartment A and prairie domains mainly in compartment B for differentiated cells 15 Interestingly, the latter changes in the same trend as the level by which chromatin segregates, as seen in Fig. 1B.…”

“…CGI forests are DNA domains with densely distributed CGIs, identified based on neighboring CGI distance distributions along the genome. A CGI forest was then defined as a continuous DNA region longer, and inside which all neighboring CGI distances are shorter, than a critical distance 15 . CGI prairie domains are the complements to forests excluding the longest chromosomal gap where the centromeres locate.…”

“…In our previous study 15 , based on the division of the mouse genome into forest and prairie domains, we defined the segregation ratio # as the inter-domain contact ratio between domains of the same types and different types (see methods). A higher # for a sample indicates a higher degree of segregation of same type-genomic domains.…”

“…(low GC content regions of forests or high GC content regions of prairies 15 ). Moreover, both forest components (Af and Bf) have higher GC contents than the two prairie components (Ap and Bp) before the 2-cell stage, whereas the two compartment A components (Af and Ap) have higher GC contents than the two components of compartment B (Bf and Bp) after the 2-cell stage.…”

“…More interestingly, the two domains spatially segregate to different extents according to cell types. Along with the progressive maturation of the higher-order chromatin architecture during embryonic preimplantation development, the two domains show an increased level of segregation from each other 2,3,15 . We pointed out that the continuous mitosis resembles a repeated annealing process for the chromatin structure to evolve towards states which probably adapt to the local cellular environment.…”