Abstract
While genetic variation at chromatin loops is relevant for human disease, the relationships between contact propensity (the probability that loci at loops physically interact), genetics, and gene regulation are unclear. We quantitatively interrogate these relationships by comparing Hi-C and molecular phenotype data across cell types and haplotypes. While chromatin loops consistently form across different cell types, they have subtle quantitative differences in contact frequency that are associated with larger changes in gene expression and H3K27ac. For the vast majority of loci with quantitative differences in contact frequency across haplotypes, the changes in magnitude are smaller than those across cell types; however, the proportional relationships between contact propensity, gene expression, and H3K27ac are consistent. These findings suggest that subtle changes in contact propensity have a biologically meaningful role in gene regulation and could be a mechanism by which regulatory genetic variants in loop anchors mediate effects on expression.
Highlights
While genetic variation at chromatin loops is relevant for human disease, the relationships between contact propensity, genetics, and gene regulation are unclear
From the eleven induced pluripotent stem cells (iPSCs) and 13 iPSC-CM samples, we generated chromatin interaction data via in situ Hi-C2. From these and other iPSC and iPSC-CM samples from the same seven individuals, we integrated functional genomic data that was generated as part of a concurrent manuscript[31] (RNA-seq for gene expression, H3K27ac ChIP-seq for enhancer activity, and ATAC-seq for chromatin accessibility; Fig. 1b; see Methods) which describes the differentiation efficiency and quality of all iPSC and iPSC-CM lines used in this study
We examined whether the 114 genome-wide significant haplotypeassociated chromatin loops (HTALs) were statistically more likely to be a specific type of loop, or overlap genomic features previously shown to be associated with differential chromatin looping
Summary
While genetic variation at chromatin loops is relevant for human disease, the relationships between contact propensity (the probability that loci at loops physically interact), genetics, and gene regulation are unclear. For the vast majority of loci with quantitative differences in contact frequency across haplotypes, the changes in magnitude are smaller than those across cell types; the proportional relationships between contact propensity, gene expression, and H3K27ac are consistent These findings suggest that subtle changes in contact propensity have a biologically meaningful role in gene regulation and could be a mechanism by which regulatory genetic variants in loop anchors mediate effects on expression. A genome-wide quantitative analysis into allele-specific chromatin looping using phased Hi-C would enable the unbiased estimation of the magnitude at which contact propensity varies across haplotypes at all types of chromatin loops (rather than only those at promoters and/or enhancers) Integrating this data with phased gene expression and H3K27ac data could provide evidence that contact propensity plays a role in long-range gene expression regulation, and provide insight into how regulatory genetic variants may influence chromatin structure. This model suggests that regulatory genetic variation could mediate its effects on gene expression through subtle modification of contact propensity at chromatin loops
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