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Title: Analysis of non-coding RNA's in the Beta-globin locus
Author: Caley, Daniel Paul
ISNI:       0000 0004 2744 0321
Awarding Body: Oxford Brookes University
Current Institution: Oxford Brookes University
Date of Award: 2012
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Human haemoglobin is made up of two types of proteins called alpha and beta-globin. The β-Globin locus, located on chromosome 11, is 100kb in length and comprises five globin genes (HBE, HBG1, HBG2, HBBPl [a pseudogene], HBD and HBB). These genes are arranged in the same order as their expression occurs during the course of development from an embryo to neonate. However the mechanism that controls the switching between globin genes during development is unknown. A zinc finger transcription factor called Bcllla is known to reduce the levels of HbF but it is unclear how this effect is ... coding RNA's (ncRNA), such as XIST, HOTAIR and HOTTIP ... been shown to control the activity of genes by forming complexes with proteins that either increase or decrease gene expression. Bcllla does not bind directly to any of the genes in the β-globin locus, but it does appear to bind to a region called BGL3, situated between HBGl and HBBP1, which encodes a non-coding RNA. This raises the question of whether the BGL3 transcript plays a role in globin switching. The work presented in this thesis aims to characterise this ncRNA and test whether it plays a direct functional role in Bcllla-mediated HbF repression. siRNA-mediated knockdowns of BGL3 in an erythroid cell line, K562, led to a statistically significant reduction in the steady state levels of BGL3 (0.0053), HBG2 (0.0314) and the pseudogene HBBPl (0.0003). Over-expression of Bcllla in the same cell system led to a dramatic reduction in BGL3, HBG2 and HBBP1. Based on these data a new model of HbF to Hba switching is proposed: In the HbF stage BGL3 is expressed, recruiting chromatin modifying complexes, which activate the HBG1, HBG2 and HBBPl genes. During the switch to Hba, Bcllla
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available