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
  • 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
  • Zebrafish
PubMed
32663239 Full text @ Blood
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
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping