Enhancer-gene rewiring in the pathogenesis of Quebec platelet disorder

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder with a unique, platelet-dependent, gain-of-function defect in fibrinolysis, without systemic fibrinolysis. The hallmark feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes. This overexpressi...

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Bibliographic Details
Published in:Blood 2020-12, Vol.136 (23), p.2679-2690
Main Authors: Liang, Minggao, Soomro, Asim, Tasneem, Subia, Abatti, Luis E., Alizada, Azad, Yuan, Xuefei, Uusküla-Reimand, Liis, Antounians, Lina, Alvi, Sana Akhtar, Paterson, Andrew D., Rivard, Georges-Étienne, Scott, Ian C., Mitchell, Jennifer A., Hayward, Catherine P.M., Wilson, Michael D.
Format: Article
Language:English
Subjects:
Animals
Enhancer Elements, Genetic
Factor V Deficiency - genetics
Factor V Deficiency - metabolism
Factor V Deficiency - pathology
Female
Gene Duplication
Gene Expression Regulation
Humans
Megakaryocytes - metabolism
Megakaryocytes - pathology
Membrane Proteins - biosynthesis
Membrane Proteins - genetics
Platelets and Thrombopoiesis
Zebrafish
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Summary:Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder with a unique, platelet-dependent, gain-of-function defect in fibrinolysis, without systemic fibrinolysis. The hallmark feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes. This overexpression leads to a >100-fold increase in platelet stores of urokinase plasminogen activator (PLAU/uPA); subsequent plasmin-mediated degradation of diverse α-granule proteins; and platelet-dependent, accelerated fibrinolysis. The causative mutation is a 78-kb tandem duplication of PLAU. How this duplication causes megakaryocyte-specific PLAU overexpression is unknown. To investigate the mechanism that causes QPD, we used epigenomic profiling, comparative genomics, and chromatin conformation capture approaches to study PLAU regulation in cultured megakaryocytes from participants with QPD and unaffected controls. QPD duplication led 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 blood disorder phenotype. •Duplication of PLAU in QPD disrupts genome architecture and rewires enhancer-gene interactions, causing cell type–specific overexpression. [Display omitted]
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2020005394