Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder

Quebec Platelet Disorder (QPD) is an autosomal dominant bleeding disorder caused by a 78kb tandem duplication of PLAU and is characterized by >100-fold increased levels of urokinase plasminogen activator (PLAU) transcripts and protein in megakaryocytes/platelets but not leukocytes, without increased systemic fibrinolysis. To address the cell-type and allele-specific PLAU overexpression that underlie QPD pathogenesis,we used epigenomic profiling, comparative genomics and chromatin conformation capture approaches to study PLAU regulation in cultured megakaryocytes. We show that the QPD duplication leads to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD). Our results support a unique disease mechanism whereby the reorganization of sub-TAD genome architecture results in a dramatic, cell-type specific disease phenotype.EGA study EGAS00001004315