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Title: Investigating the function of the non-coding RNAs miR-27b and Herna1 in pathologic cardiac hypertrophy
Author: Bischof, Corinne
ISNI:       0000 0004 7656 9316
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Hypoxia inducible factor 1α (Hif1α) plays a key role in the induction and maintenance of heart disease and many direct Hif1α target genes have been identified. However, a number of genes show a Hif1α-dependent expression pattern although they lack the hypoxia response element (HRE) in their promoter for direct Hif1α binding. This work identified two modes of indirect gene regulation by Hif1α via a microRNA and enhancer RNA (eRNA), respectively, and their function in pathologic cardiac hypertrophy. Hif1α regulates the alpha subunit of ATP synthase, Atp5a1, through the induction of miR-27b. ATP synthase is a component of the respiratory chain and plays a key role in energy homeostasis. ATP synthase inactivation from yeast to man promotes cell growth coincident with ATP depletion. Accumulating mitochondrial ADP is redirected to methylenetetrahydrofolate dehydrogenase 1l (Mthfd1l) to drive DNA biosynthesis, karyokinesis and pathologic growth. In vivo gain- and loss-of-function studies, and correlative analysis of diseased human cohorts, confirm these findings to reveal a novel role for mitochondrial ATP synthase in cell and tissue growth control. Hif1α promotes transcription of Hif1α-activated eRNA 1 (HERNA1) from an active enhancer locus to confer spatio-temporal and signal-dependent control of gene expression in cardiac pathologies. Production of HERNA1 is initiated by direct HIF1α binding to an HRE motif in the promoter of the enhancer and confers hypoxia responsiveness to the nearby genes synaptotagmin XVII, a family member of membrane-trafficking and Ca2+-sensing proteins and SMG1, a phosphatidylinositol 3-kinase-related kinase involved in the control of nonsense-mediated mRNA decay (NMD). HERNA1, SMG1 and SYT17 expression correlate positively with distinct aetiologies of heart disease. Finally, Herna1 promotes the shift to glycolysis, contractile dysfunction and cardiac growth through Smg1 and/or Syt17.
Supervisor: Krishnan, Jaya Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral