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Title: The role of HIRA in cardiovascular development
Author: Dilg, D. J. H.
ISNI:       0000 0004 8498 3293
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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HIRA was originally identified in the group of Peter Scambler as a candidate gene for DiGeorge syndrome and was later identified to deposit the histone variant H3.3. Constitutively null Hira embryos all die between embryonic day (E) 6.5 and 10.5, with some mutants presenting with heart defects. A conditional allele was therefore employed to examine the role of HIRA during heart development. Conditional ablation in the cardiogenic mesoderm (Mesp1Cre) led to surface oedema, ventricular septum defects (VSD) and embryonic lethality. More specific Cre drivers have shown that HIRA is essential in cardiomyocytes (Nkx2.5Cre) but is not in endothelial cells (Tie2Cre). RNAseq analysis and in situ hybridization were used to detect an upregulation of the troponins Tnni2 and Tnnt3 and a decreased expression of Epha3, a gene necessary for fusion of the interventricular septum with the endocardial cushions. In addition, immunostaining of Troponin C (TnC) emphasised a disorganisation of the contracting meshwork of myofibril. ChIPseq experiment revealed that HIRA binds to GAGA rich DNA sequence in the embryonic heart and is enriched at the common enhancer of Tnni2/Tnnt3 (TLT). Furthermore, in vitro and in vivo co-immunoprecipitations revealed that HIRA interacts with WHSC1 a protein thought to play a major role in Wolf-Hirschhorn syndrome, as well as BRG1, a chromatin remodelling complex required for cardiogenesis. WHSC1 also interacts with NKX2.5, a major cardiac transcription factor that binds the same regulatory TLT site as HIRA. Altogether, this work gives evidence for a specific requirement of HIRA in mesodermal cardiac progenitors during heart development. HIRA influences contractility, troponins expression and the endothelial to mesenchymal transition in the cardiac cushions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available