DNA sequence-dependent chromatin architecture and nuclear hubs formation

Kamel Jabbari,Maharshi Chakraborty,Thomas Wiehe

doi:10.1038/s41598-019-51036-9

Kamel Jabbari, Maharshi Chakraborty + Show 1 more

Open Access

https://doi.org/10.1038/s41598-019-51036-9

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Journal: Scientific Reports	Publication Date: Oct 10, 2019
Citations: 26	License type: open-access

Affiliation: University of Cologne

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.

Highlights

Developed chromatin conformation capture techniques and methods uncovered principles of the spatial organization of nuclear hubs and interchromosomal interactions
To study the effect of regional genomic GC level on interchromosomal interactions, including hub formation, we first used the data provided by Quinodoz et al to show that there is a strong GC enrichment of interchromosomal hubs arranged around the nuclear speckles (Fig. 1a)
These associations (Pearson r = 0.82, p-values < 2.2e−16) are observed locally along non-contiguous regions of mouse chromosome 11 reported in Quinodoz et al (Fig. 1b). These results suggest that the preferential spatial arrangement of either the nucleolus or nuclear speckle hubs can be recognized by GC level changes along chromosomes

Summary

Introduction

Developed chromatin conformation capture techniques and methods uncovered principles of the spatial organization of nuclear hubs and interchromosomal interactions. The discovery, characterization, and function of chromatin domains have been covered by a number of reviews[1,2,3,4,5] These methods revealed many features of 3D genome organization, in particular, topologically associated domains (TADs)[6,7], self-interacting regions, characterized by frequent within-chromatin interactions compared to relatively lower-frequency interactions with surrounding regions. To better understand the role of transcription activity in nuclear molecular crowding, we estimated inter- and intra-TADs gene transcriptional profiles using 27 human tissues Together, this analysis suggests that physicochemical and functional constraints affect chromatin loops formation and may induce phase separation through loop clusters interconnections. Multivalent macromolecular interactions[23] are favourably occurring in GC-rich, nucleosome free chromatin[24,25,26]

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