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Title: The role of the polycomb group gene PCGF2 in human haematopoiesis
Author: Reyal, Y.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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The self renewal of haematopoietic stem cells is a complex, tightly regulated process. One of the key players in this mechanism BMI1, which belongs to a family of proteins called the polycomb group (PcG) proteins. These form two distinct complexes, that act as chromatin modifiers to regulate gene expression. In mammals, there are several paralogues of BMI1, however their role in haematopoiesis is unclear. The expression of a panel of PcG genes was assessed in umbilical cord blood HSCs and progenitors. Several PcG genes were found to be more highly expressed in the HSCenriched CD34+ CD38- population compared to the progenitor subpopulations of cord blood cells. PCGF2, which shares high homology with BMI1 but has been reported to have a contrasting function, was chosen for further investigation. The effects of knockdown of PCGF2 were compared to those of BMI1 knockdown, using lentiviral delivery of shRNA in cord blood cells. Loss of either BMI1 or PCGF2 resulted in reduced colony formation and a reduction in the frequency of longterm culture initiating cells (LTC-IC). In primary and secondary transplantation in NSG mice, human cells with down regulated PCGF2 had reduced engraftment capacity compared to control cells. As PCGF2, like BMI1, appeared to be required by human HSCs, the question was raised as to whether the two act via the same or independent pathways. This was addressed in two ways. Global gene expression profiling of transduced cells demonstrated that different pathways are altered upon knockdown of either BMI1 or PCGF2. These results indicate that these two proteins play complementary roles. However it seems that one can also substitute for the other as overexpression of PCGF2 rescued the phenotype of BMI1 knockdown in vivo although not in vitro. It is likely that PCGF2 shares a role with BMI1 but also has unique functions. The individual contributions of the PcG proteins are likely to be complex and inter-related and warrant further investigation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available