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Title: Locus-wide studies into the transcriptional regulation of Runx1 in developmental hematopoiesis
Author: Jarratt, Andrew
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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Developmental hematopoiesis sees the generation of the first blood cells and definitive blood during embryonic development. The founding cell of definitive hematopoiesis, the hematopoietic stem cell (HSC), gives rise to all adult blood :I: ]] 1:: t '.1 '4 !..:. : 1 1 '.! . lineages throughout the the life span or an orgamism. It IS expected that future ex-vivo manipulation ofHSCs for therapeutic uses will benefit from a thorough understanding of the mechanisms, both cellular and genetic, that give rise to HSCs. One of the most critical regulators of HSC emergence in the embryo is the transcription factor (TF) Runxl. One aim of our lab is to decipher what controls the cis-regulation of Runxl to understand better how it exerts its function in the emergence of HSCs. In this thesis, chromatin assays were used to identify putative enhancers within the 1.3 Mb Runxl syntenic region. Seven novel enhancers were identified that mediate reporter gene expression in discrete patterns of Runx1-specific hematopoietic expression in transient transgenic embryos. Characterization of the cells marked by one of these enhancers, the + 11 0 enhancer in a transgenic mouse line, showed that it is active in clonogenic progenitors at Ell.5, but, interestingly, not HSCs. Finally, chromosome conformation capture (3C) assays showed physical interactions between the Runxl PI and P2 promoters and between the Runxl PI and P2 promoters and putative regulatory elements in the 1.3 Mb syntenic region. Together, these data increase our understanding of the complexity of Runxl cis-regulation during development and provide a starting point for characterizing what upstream trans-acting factors converge on Runxl to specify blood.
Supervisor: Bruijn, Marella Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available