Fine-Scale Genome Folding Relative to Transcription and Location

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ABSTRACT The human genome is precisely folded into various structures, which provides the context for functional processes in the nucleus. Recent advances have indicated the presence of chromatin compartments, CTCF loops, and small gene-loops as prevalent features of genome organization. Our investigations at high resolution reveal the presence of sub-genic discordant compartments, placing the 5’ and 3’ ends of many genes in opposite compartment states. These, along with gene-loops, are highly correlated with transcription elongation status, but how transcription influences these sub-genic structures is unknown. Additionally, the spatial location of these features is an important aspect of genome organization that is largely ignored, and which of these features are dependent on radial location is unclear. The goals of our research are to determine the relationship between transcription and sub-genic scale chromatin organization and to elucidate the impact of spatial location on chromatin folding. We will accomplish these goals in programs that use (1) basic mechanistic interrogation to track how sub-genic structures change as transcription progresses, (2) software development for increased sensitivity and quantitative fidelity in fine-scale compartment analysis, and (3) investigative genomics to enrich for peripheral interactions and define the relationship between chromatin contacts and radial position. The results of this research will resolve mechanistic questions surrounding transcription and gene folding, provide new sorely needed and cost-saving tools for fine-scale analysis, and identify spatially dependent chromatin organization.