Abstract
Chromatin interactions are important for gene regulation and cellular specialization. Emerging evidence suggests many-body spatial interactions play important roles in condensing super-enhancer regions into a cohesive transcriptional apparatus. Chromosome conformation studies using Hi-C are limited to pairwise, population-averaged interactions; therefore unsuitable for direct assessment of many-body interactions. We describe a computational model, CHROMATIX, which reconstructs ensembles of single-cell chromatin structures by deconvolving Hi-C data and identifies significant many-body interactions. For a diverse set of highly active transcriptional loci with at least 2 super-enhancers, we detail the many-body functional landscape and show DNase accessibility, POLR2A binding, and decreased H3K27me3 are predictive of interaction-enriched regions.
Highlights
Chromosome folding and nuclear organization play essential roles in fundamental processes such as regulation of gene expression [1, 2] and cellular specialization [3, 4]
We extend the approach of Gürsoy et al by using the method of fractal Monte Carlo weight enrichment to uniform randomly sample an ensemble of ∼ 400, 000 3-D polymer conformations
Our CHROMATIX framework can identify specific many-body chromatin interactions, and we show the predicted manybody interactions to be broadly concordant with SPRITE clusters
Summary
Chromosome folding and nuclear organization play essential roles in fundamental processes such as regulation of gene expression [1, 2] and cellular specialization [3, 4]. A wealth of information on chromatin organization has been gained through studies based on chromosome conformation capture techniques such as Hi-C [5–8], which measure pairwise, proximity interactions between chromatin regions that are averaged over a population of cells [6, 9]. There is growing evidence that multivalent interactions play important roles in formation of phase-separated and highly dense, functional chromatin assemblies in super-enhancers (SEs) [10, 11]; it is difficult to detect and quantify many-body (≥ 3) interactions from pairwise and averaged Hi-C measurements. Several experimental techniques have been developed to detect putative many-body chromatin interactions These include single-cell Hi-C [12–14], Dip-C [15, 16], Tri-C [2], GAM [17], and SPRITE [18]. Our current knowledge of many-body chromatin interactions and their functional roles in chromatin condensation is limited
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