DNA sequence-dependent chromatin architecture and nuclear hubs formation

Abstract

In this study, by exploring chromatin conformation capture data, we show that the nuclear segregation of Topologically Associated Domains (TADs) is contributed by DNA sequence composition. GC-peaks and valleys of TADs strongly influence interchromosomal interactions and chromatin 3D structure. To gain insight on the compositional and functional constraints associated with chromatin interactions and TADs formation, we analysed intra-TAD and intra-loop GC variations. This led to the identification of clear GC-gradients, along which, the density of genes, super-enhancers, transcriptional activity, and CTCF binding sites occupancy co-vary non-randomly. Further, the analysis of DNA base composition of nucleolar aggregates and nuclear speckles showed strong sequence-dependant effects. We conjecture that dynamic DNA binding affinity and flexibility underlay the emergence of chromatin condensates, their growth is likely promoted in mechanically soft regions (GC-rich) of the lowest chromatin and nucleosome densities. As a practical perspective, the strong linear association between sequence composition and interchromosomal contacts can help define consensus chromatin interactions, which in turn may be used to study alternative states of chromatin architecture.