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Genome-wide mapping and analysis of chromosome architecture in human tissues

Abstract

Gene expression in mammals is regulated by complex networks involving higher order chromatin organization, transcription factor binding, histone and DNA biochemical modifications, as well as other mechanisms. Our understanding of the functional relationship between 3D chromosome architecture and gene regulation has been limited by the technologies to map 3D chromatin looping and the breadth of cell or tissue types analyzed. During my Ph.D. I have addressed technological shortcomings in the field by developing a high-resolution method for mapping chromatin interaction profiles at thousands of loci in a single assay, termed Capture-HiC. We have shown that Capture-HiC is capable of obtaining interaction profiles for contiguous loci, and when used in conjunction with HaploSeq phasing technology, can obtain targeted haplotype phasing information for medically relevant loci such as the MHC and KIR loci. Also during my Ph.D. I have greatly advanced our understanding of the functional relationship between chromatin organization and gene regulation through Hi-C analysis across 21 human cell lines and primary adult tissues. We have discovered that chromosome architecture in human tissues exhibits distinguishing signatures of local spatially active regions. These regions, termed FIREs, are highly tissue-specific, enriched for active enhancers and GWAS variants, and conserved between human and mouse. We also find that FIREs exhibit promiscuous local interaction behavior and a significant degree of self-interaction. Further, I have developed high-resolution promoter Capture-HiC technology, and used this to map promoter-centered long-range interactomes in 27 human cell and tissue types. We find that promoter-centered interactions in tissues lie within dynamic interaction networks, which cluster by developmental lineage. Most surprisingly, we find widespread promoter-promoter interactions that impact distal gene expression, including hundreds of promoter regions harboring GWAS variants that have functional implications on distal genes. Together, through Hi-C and Capture-HiC analyses in human tissues, we have developed a rich resource for understanding chromatin folding and gene regulation. We anticipate these studies to lay a foundation for future experiments designed to further understand the function of complex chromatin looping events as well as the future study of how deleterious variants in cis-regulatory elements perturb gene regulation.

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