Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.800133
Title: Integrating chromatin and development : LDB1 regulates genome architecture and gene expression in motor neuron differentiation
Author: Demmerle, Justin
ISNI:       0000 0004 8507 7401
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Abstract:
Dynamic changes in chromatin architecture underpin gene expression in development. The chromatin integrator protein LDB1 is a key regulatory node in the organization of developmentally-specific gene expression programs, particularly in motor neurons (MNs) of the vertebrate spinal cord. By coordinating transcription factor binding, chromatin remodeling, and 3D genome organization, LDB1 is an essential chromatin integrator protein in the development of MNs. In this thesis I characterise the deletion of LDB1 in an in vitro MN differentiation system in the mouse. By measuring transcription factor (TF) binding, protein association, gene expression, and 3D-genome organization, I specify the genetic elements that LDB1 regulates. I find that LDB1 regulates binding of the promiscuous TFs Isl1 and Lhx3 at a subset of critical MN genes, specified particularly in cooperation with the LDB1 binding partner SSDP1, where it drives open chromatin, H3K27ac deposition, gene expression, and likely enhancer function. Thus, LDB1 integrates multiple levels of specificity to regulate dozens of genes and enhancers that are critical to the expression of MN genes. I propose that this is a key feature of spatial genome regulation and is mediated by LDB1 and the interaction with its binding partner SSDP1. I identify a minimal set of MN-specific genes regulated by LDB1, as well as a set of elements that regulate subtle features of 3D genome organization and transcription. Together, I establish LDB1 as a critical regulator of 3D genome organization, transcription factor assembly, and gene expression, making LDB1 and genes downstream of its effects into promising targets for improved cellular reprogramming strategies.
Supervisor: Schermelleh, Lothar ; Macfarlan, Todd Sponsor: National Institutes of Health
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.800133  DOI: Not available
Keywords: Microscopy ; LIM Domain Proteins ; Molecular Biology ; Transcription Factors ; Developmental Biology ; Motor Neurons ; Genomics
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