Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder

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 >100-fold increased platelet stores of urokinase plasminogen activator (PLAU/uPA), subsequent plasmin-mediated degradation of diverse a-granule proteins, and platelet-dependent, accelerated fibrinolysis. The causative mutation is a 78kb 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 QPD participants and unaffected controls. 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 subTAD genome architecture results in a dramatic, cell-type specific blood disorder phenotype.

Whole genome sequencing identifies common and rare structural variants contributing to hematologic traits in the NHLBI TOPMed program

“…GWAS have identified thousands of SNVs and small indels that contribute to quantitative hematologic traits but the contribution of SVs to blood cell trait variation has mainly been limited to individuals with rare genetic blood disorders [33][34][35] . Here we investigated the contribution of SVs to hematologic variation in ancestrally diverse TOPMed participants.…”

Update on platelet procoagulant mechanisms in health and in bleeding disorders

“…Abnormalities in platelet but not plasma factor V, affecting platelet dependent prothrombinase function, also occur in QPD, an autosomal dominant bleeding disorder affecting fibrinolysis that was originally called factor V Quebec when the platelet factor V abnormalities were discovered 80 . The molecular cause of QPD is tandem duplication of a 78‐kb region on chromosome 10 that includes PLAU and repositions a megakaryocyte‐specific VCL enhancer upstream of a copy of PLAU on the disease chromosome so that PLAU is rewired and exhibits aberrant, marked increased expression during megakaryocyte differentiation 81 . The result is a unique, platelet‐dependent gain‐of‐function defect in fibrinolysis, reflecting >100‐fold increased megakaryocyte/platelet levels of urokinase plasminogen activator (uPA), but minimal changes to plasma, leukocyte and urinary uPA levels 82 .…”

Heart Enhancers: Development and Disease Control at a Distance

“…While evolutionarily conserved TADs correspond to regions of conserved synteny harboring important developmental genes and enhancers (Harmston et al, 2017), new analyses have questioned the extent to which TAD boundaries themselves correspond to evolutionary breakpoints (Eres et al, 2019;Eres and Gilad, 2020;Torosin et al, 2020). The importance of understanding how TADs relate to gene regulation is underscored by the increasing number of experiments showing that the disruption of TAD boundaries and sub-TAD domains can rewire enhancer-promoter interactions and fundamentally change the regulatory environment (Guo et al, 2015;Lupiáñez et al, 2015;Flavahan et al, 2016;Franke et al, 2016;Liang et al, 2020).…”