Hi-C Derived Data For Haplotype Three-dimensional Structure And Function Analysis

With the growth of sequencing technology, international research projects such as 1000 Genomes and Hap Map have launched studies regarding haplotypes, including haplotype assembly, allele-specific expression and parental transmission-related sequence variation. These projects show that haplotypes exhibit individual differences, group preferences, and disease regulation potential, deepening our understanding regarding haplotypes and their functions. Additionally, the latest Hi-C and FISH experiments have revealed that homologous chromosomes occupy relatively independent spatial domains in the nucleus, forming chromosome territories during cell division. The latest experiments have also demonstrated that the three-dimensional spatial structure of chromatin plays an important role in regulating gene expression. Taken together, these results imply that the three-dimensional structures of haplotypes have important roles in biological functions; thus, the characteristics and regulation of haplotypes should be studied in three-dimensional space. Specifically, the three-dimensional structural differences between homologous chromosomes, the potential molecular mechanisms of these differences, and their effects on regulating allele-specific expression should be examined.To explore these problems, this dissertation studied the structural characteristics and regulatory functions of haplotypes in human and mouse species using Hi-C data. First, this dissertation built a computational pipeline to process allele-specific Hi-C chromatin interaction data. Our pipeline can effectively determine reliable haplotype chromatin interactions based on SNPs that have been built by Hap Map and 1000 Genome Projects. Second, this dissertation discussed the effect of sequence variation on the three-dimensional structures of haplotypes. We found that DNA variations in gene-rich regions or mutations involving C and G bases have greater effects on chromatin structural reorganization, suggesting the effect of specific DNA variations on the three-dimensional structures of haplotypes. Finally, to investigate the molecular mechanisms of the effects of DNA variations on three-dimensional structural changes and their regulatory roles in allele-specific expression further, this dissertation presents a correlation analysis between allele-specific chromatin interactions and allele-specific transcription factor binding, epigenetic modifications and gene expression. The significant correlations found imply that the DNA variation-induced regulatory changes, particularly TF binding and epigenomic modifications, can result in reorganizing haplotype enhancer-promoter chromatin interactions, which eventually lead to allele-specific expression.