Enhancer-gene rewiring in the pathogenesis of Quebec platelet disorder.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
03 12 2020
03 12 2020
Historique:
received:
28
04
2020
accepted:
06
07
2020
pubmed:
15
7
2020
medline:
7
4
2021
entrez:
15
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32663239
pii: S0006-4971(20)81963-6
doi: 10.1182/blood.2020005394
pmc: PMC7735161
doi:
Substances chimiques
Membrane Proteins
0
PLAU protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2679-2690Subventions
Organisme : CIHR
ID : 201603PJT-364832
Pays : Canada
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 by The American Society of Hematology.
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