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


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.


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.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:molecular biology; RNA; genome organization; splicing; biochemistry; nucleus; nuclear bodies; genome structure; nuclear structure; noncoding RNA; nuclear speckle; genomics
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Molecular Biology
Minor Option:Biochemistry
Awards:Everhart Distinguished Graduate Student Lecturer Award, 2023.
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Guttman, Mitchell
Thesis Committee:
  • Elowitz, Michael B. (chair)
  • Baltimore, David L.
  • Guttman, Mitchell
  • Chang, Howard Y.
  • Black, Douglas L.
Defense Date:3 May 2023
Funding AgencyGrant Number
Josephine de Karman Fellowship TrustUNSPECIFIED
Chen Graduate Innovator Grant AwardUNSPECIFIED
NRSA F30 (National Cancer Institute)F30CA247447
Record Number:CaltechTHESIS:05302023-040856946
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Ch. 1: Nuclear compartmentalization as a mechanism of quantitative control of gene expression adapted for Ch. 2: RNA promotes the formation of spatial compartments in the nucleus adapted for Ch. 4: 3D genome organization around nuclear speckles drives mRNA splicing efficiency
Bhat, Prashant0000-0003-3832-4871
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:15229
Deposited By: Prashant Bhat
Deposited On:01 Jun 2023 16:12
Last Modified:08 Nov 2023 18:03

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