Delineating the interplays between 3D genomic organization and transcriptional regulation
2School of Computer Science, Tel Aviv University
3Department of Molecular and Cell Biology, University of California, Berkeley, USA
Over the past decade, investigation of the 3D organization of the genome and its functional roles has been advancing rapidly, revolutionized by the maturation of the Hi-C technique. Hi-C studies reveal a multi-layer structural hierarchy of the genome spatial organization. At the top of the hierarchical organization are chromosomal territories and the megabase-scale A/B compartments that were shown to correlate with transcriptional activity and chromatin compaction within cells. Nested within compartments are the relatively cell-type invariant topologically associated domains (TADs), characterized by high frequency of physical contacts between all loci within the same TAD and low frequency of interactions across TAD boundaries. Thus, assumed to function as isolated regulatory units. Within the TADs scaffold, chromatin loops bring enhancers and target promoters to close spatial proximity. Nevertheless, we still have only rudimentary understanding about how alterations in different layers of chromatin organization, including rewiring of enhancer-promoter (E-P) links, affect cell-type specific gene expression programs.
In this study, we analyze chromatin interaction data from 10 different cell lines, generated using the micro-C method, a Hi-C variant with improved resolution, combined with RNA-seq data, to investigate the reciprocal relations between chromatin folding and gene expression. We demonstrate widespread correlation, over a panel of cell types, between contact propensity of E-P loops and the expression level of the target genes. We identified dozens of cell-type specific E-P loops that correlate with the expression of genes that carry cell-type specific functions. This analysis illuminates chromatin loops as a critical quantitative gene expression regulatory mechanism.