PUBLICATION
Enhancer-gene rewiring in the pathogenesis of Quebec platelet disorder
- Authors
- Liang, M., Soomro, A., Tasneem, S., Abatti, L.E., Alizada, A., Yuan, X., Uusküla-Reimand, L., Antounians, L., Alvi, S.A., Paterson, A.D., Rivard, G.É., Scott, I.C., Mitchell, J.A., Hayward, C.P.M., Wilson, M.D.
- ID
- ZDB-PUB-210407-78
- Date
- 2020
- Source
- Blood 136: 2679-2690 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Factor V Deficiency*/genetics
- Factor V Deficiency*/metabolism
- Factor V Deficiency*/pathology
- Humans
- Gene Expression Regulation*
- Female
- Gene Duplication*
- Zebrafish
- Animals
- Membrane Proteins*/biosynthesis
- Membrane Proteins*/genetics
- Megakaryocytes/metabolism*
- Megakaryocytes/pathology
- Enhancer Elements, Genetic*
- PubMed
- 32663239 Full text @ Blood
Citation
Liang, M., Soomro, A., Tasneem, S., Abatti, L.E., Alizada, A., Yuan, X., Uusküla-Reimand, L., Antounians, L., Alvi, S.A., Paterson, A.D., Rivard, G.É., Scott, I.C., Mitchell, J.A., Hayward, C.P.M., Wilson, M.D. (2020) Enhancer-gene rewiring in the pathogenesis of Quebec platelet disorder. Blood. 136:2679-2690.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping