Genomic meta-analysis of the interplay between 3D chromatin organization and gene expression programs under basal and stress conditions

Abstract

BackgroundOur appreciation of the critical role of the 3D organization of the genome in gene regulation is steadily increasing. Recent 3C-based deep sequencing techniques elucidated a hierarchy of structures that underlie the spatial organization of the genome in the nucleus. At the top of this hierarchical organization are chromosomal territories and the megabase-scale A/B compartments that correlate with transcriptional activity within cells. Below them are the relatively cell-type invariant topologically associated domains (TADs), characterized by high frequency of physical contacts between loci within the same TAD and are assumed to function as regulatory units. Within TADs, chromatin loops bring enhancers and target promoters to close spatial proximity. Yet, we still have only rudimentary understanding how differences in chromatin organization between different cell types affect cell-type specific gene expression programs that are executed under basal and challenged conditions.\n\nResultsHere, we carried out a large-scale meta-analysis that integrated Hi-C data from thirteen different cell lines and dozens of ChIP-seq and RNA-seq datasets measured on these cells, either under basal conditions or after treatment. Pairwise comparisons between cell lines demonstrated the strong association between modulation of A/B compartmentalization, differential gene expression and transcription factor (TF) binding events. Furthermore, integrating the analysis of transcriptomes of different cell lines in response to various challenges, we show that 3D organization of cells under basal conditions constrains not only gene expression programs and TF binding profiles that are active under the basal condition but also those induced in response to treatment.\n\nConclusionsOur results further elucidate the role of dynamic genome organization in regulation of differential gene expression between different cell types, and indicate the impact of intra-TAD enhancer-promoter interactions that are established under basal conditions on both the basal and treatment-induced gene expression programs.