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Title: Transcriptional regulation at the angiogenic sprout
Author: Chouliaras, Kira
ISNI:       0000 0004 8503 0240
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Angiogenesis, the formation of new blood vessels from existing ones, depends on very precise spatio-temporal gene expression patterns in different sub-types of endothelial cells. These patterns are controlled by pro-angiogenic stimuli but the transcriptional mechanism by which these stimuli induce specific gene expression in endothelial cells is not well understood. In this thesis I identify and characterize a novel sprouting-specific enhancer upstream of the angiogenesis-specific H2.0-like homeobox protein (HLX/hlx) gene. This conserved enhancer, termed HLX-3/hlx-3, is able to direct gene expression specifically and selectively to angiogenic endothelial cells in both transgenic zebrafish and mice during physiological and pathological angiogenesis. Analysis of the transcription factor binding sites within the HLX-3/hlx-3 enhancer reveals a requirement for myocyte enhancer factor-2 (MEF2) family members for enhancer activity. Endothelial-specific Mef2A/C knockout results in reduced sprouting in the mouse retina, confirming an important role for MEF2 factors in the regulation of both Hlx and sprouting angiogenesis more generally. Further, I use the hlx-3:GFP transgenic zebrafish line to generate a genome-wide map of accessible chromatin regions from isolated sprouting cells, and compare them to arterial and venous endothelial cells. My results demonstrate that accessible chromatin is not sufficient to reliably predict enhancer activity patterns, and that within the endothelial-lineage, regulatory elements are constitutively open irrespective of the sub-endothelial cell type. Interestingly, despite these observations, binding motifs for MEF2C and angiogenic-associated transcription factors are enriched in sprouting endothelial cells. These results provide novel insights into the transcriptional regulatory landscape of endothelial cells and confirm the importance of MEF2 factors during angiogenesis.
Supervisor: Val, Sarah De ; Goding, Colin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available