On the Role of Three-Dimensional Genome Organization in Gene Regulation and mRNA Splicing

Citation

Bhat, Prashant (2023) On the Role of Three-Dimensional Genome Organization in Gene Regulation and mRNA Splicing. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/vg8a-y851. https://resolver.caltech.edu/CaltechTHESIS:05302023-040856946

Abstract

The nucleus is spatially organized such that DNA, RNA, and protein molecules involved in shared functional and regulatory processes are compartmentalized in three-dimensional (3D) structures. These structures are emerging as a paradigm for gene regulation, a highly complex process that requires the dynamic coordination of hundreds of regulatory factors around precise targets in different cell states. We describe the discovery of hundreds of RNA-DNA hubs throughout the nucleus that are organized around essential nuclear functions such as RNA processing, centromeric heterochromatin organization, and gene regulation. Focusing on RNA processing, specifically co-transcriptional splicing, we find that genome-wide organization of active genes near nuclear speckles drives the efficiency of pre-mRNA splicing in a cell-type specific manner. The results of this thesis illustrate how spatial compartmentalization of biomolecules increases the local concentration of reactants and enzymes such that greater efficiency is achieved in scenarios where rapid responses are required for cell survival.

Thesis Files