Widespread allele-specific topological domains in the human genome are not confined to imprinted gene clusters.

Abstract

BackgroundThere is widespread interest in the three-dimensional chromatin conformation of the genome and its impact on gene expression. However, these studies frequently do not consider parent-of-origin differences, such as genomic imprinting, which result in monoallelic expression. In addition, genome-wide allele-specific chromatin conformation associations have not been extensively explored. There are few accessible bioinformatic workflows for investigating allelic conformation differences and these require pre-phased haplotypes which are not widely available. ResultsWe assembled a bioinformatic pipeline, "HiCFlow", which performs haplotype assembly and visualisation of parental chromatin architecture. We benchmarked the pipeline using prototype haplotype phased Hi-C data from GM12878 cells at three disease associated imprinted gene clusters. Using RC-HiC (Region Capture Hi-C) and Hi-C data from further human cell lines (1-7HB2, IMR-90, and H1-hESCs) we were able to robustly identify the known stable allele-specific interactions at the H19/IGF2 locus. Other imprinted loci (DLK1 and SNRPN) were more variable and there was no "canonical imprinted 3D structure", but we could detect allele-specific differences in A/B compartmentalisation. Genome-wide, when TADs were unbiasedly ranked according to their allele-specific contact frequencies, a set of "allele-specific TADs" (ASTADs) could be defined. These occurred in genomic regions of high sequence variation. In addition to imprinted genes, ASTADs were also enriched for allele-specific expressed (ASE) genes. We found loci in ASTADs that have not previously been identified as ASE such as the bitter taste receptors (TAS2Rs). ConclusionsThis study highlights the widespread differences in chromatin conformation between heterozygous loci and provides a new framework for understanding ASE.