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Title: Regulation of BCL6:p38 MAPK signalling and CTCF transcriptional regulation converge at exon 1
Author: Batlle, Ana
ISNI:       0000 0004 2690 6441
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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BCL6 is a zinc finger transcriptional repressor, which is highly expressed in germinal centre B-cells, and is essential for germinal centre formation and T-dependent antibody responses. Deregulated BCL6 expression is associated with certain non- Hodgkin’s lymphomas. High expression is observed in breast cancer. Tight lineage and temporal regulation of BCL6 is, therefore, required for normal immunity and abnormal regulation occurs in cancer. Regulatory mechanisms have been analysed in two settings. Firstly, BCL6 is strongly induced by the tyrosine kinase inhibitor, Imatinib, in chronic myeloid leukaemia lymphoid blast crisis cell lines, and this effect was used in order to study the effects of phospho-protein signalling on BCL6 expression and a major finding is that p38 MAPK induced BCL6. Also, p38 is, at least in part, responsible for BCL6 expression in basal conditions in the germinal centre representative Burkitt’s lymphoma cell lines and that qualitatively different CD40 stimuli can either induce or repress BCL6 expression. Luciferase assays showed that p38 acts at a 300bp sequence immediately 5’ of exon 1, and probably also at more distal sequences. Overall it appears that the balance between positive and negative regulatory controls BCL6 expression with inhibitory signalling pathways being predominant in most circumstances. Focusing on BCL6 exon 1, a binding site for the multifunctional regulator CTCF was identified. CTCF interacts in vitro and in vivo with this sequence. Reduced expression of CTCF in germinal centre cells caused a moderate reduction of BCL6 expression. Finally, although no clear differences were observed in the methylation status of the CTCF binding site on exon 1, a significant enrichment of active histone modifications at this site was observed in BCL6 expressing cells, suggesting that CTCF may have a role in the epigenetic regulation of BCL6.
Supervisor: Wagner, Simon D. ; Porter, Andy ; Delgado, M. Dolores Sponsor: Foundation Marqués de Valdecilla and Amgen
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral