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

Idan Nurick, Ron Shamir, Ran Elkon

Our appreciation of the critical role of the genome's 3D organization 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. Here, 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 demonstrate a 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 A/B compartmentalization of cells under basal conditions significantly correlates not only with gene expression programs and TF binding profiles that are active under the basal condition but also with those induced in response to treatment. Yet, in pairwise comparisons between different cell lines, we find that a large portion of differential TF binding and gene induction events occur in genomic loci assigned to A compartment in both cell types, underscoring the role of additional critical factors in determining cell-type-specific transcriptional programs. Our results further indicate the role of dynamic genome organization in regulation of differential gene expression between different cell types and the impact of intra-TAD enhancer-promoter interactions that are established under basal conditions on both the basal and treatment-induced gene expression programs.