Quebec platelet disorder (QPD) is a bleeding disorder characterized by a gain of function defect in fibrinolysis. The hallmark feature of QPD is the marked overexpression of urokinase plasminogen activator (uPA) in megakaryocytes (MK) and platelets. The genetic cause of QPD is a tandem duplication of a ~78 kb region that encompasses the uPA gene, PLAU. As the mechanism of PLAU overexpression is unknown, gene regulatory mechanisms specifically epigenetics were evaluated at the PLAU locus in QPD MK and granulocytes, a QPD unaffected lineage. The aims of the thesis were to assess if QPD is associated with 1) genome wide methylation changes of promoter CpG islands, particularly at PLAU and 2) genome wide changes of active histone modifications H3K27Ac, H3K36me3 and H3K4me2, particularly at the region of PLAU duplication. Methylation and active histone enrichment analysis revealed that in QPD and control subjects, PLAU promoter CpG island was characterized by unaltered hypo-methylation and changes in active histone peak enrichments that were within the realm of having one extra copy of PLAU in both MK and granulocytes. The findings imply that the PLAU CNV mutation does not induce altered promoter methylation status and/or significantly alter active histone markers as the reason for the marked PLAU overexpression in QPD MK. Instead, the rearrangement of an active enhancer element, particularly an H3K27Ac enhancer expressed in MK but not granulocytes, that is upstream of the second copy of PLAU might underlie the marked PLAU expression by differentiated QPD MK. The thesis provides novel insights into the epigenetic regulation of PLAU that will be crucial to identifying the mechanism underlying the aberrant PLAU expression in QPD. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/19026 |
| Date | January 2016 |
| Creators | Soomro, Asim |
| Contributors | Hayward, Catherine P.M., Medical Sciences (Blood and Cardiovascular) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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