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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 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.

SUBMITTER: Liang M

PROVIDER: S-EPMC7735161 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder

Project description:Quebec Platelet Disorder (QPD) is an autosomal dominant bleeding disorder caused by a 78kb tandem duplication of PLAU and is characterized by >100-fold increased levels of urokinase plasminogen activator (PLAU) transcripts and protein in megakaryocytes/platelets but not leukocytes, without increased systemic fibrinolysis. To address the cell-type and allele-specific PLAU overexpression that underlie QPD pathogenesis,we used epigenomic profiling, comparative genomics and chromatin conformation capture approaches to study PLAU regulation in cultured megakaryocytes. 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 sub-TAD genome architecture results in a dramatic, cell-type specific disease phenotype.

| EGAS00001004315 | EGA

DAC for Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder

Project description:Data Access Committee EGAC00001001529

| EGAC00001001529 | EGA

Thrombin generation abnormalities in Quebec platelet disorder.

Project description:IntroductionCalibrated automated thrombograms (CAT) with platelet-poor (PPP) and platelet-rich plasma (PRP) have provided useful insights on bleeding disorders. We used CAT to assess thrombin generation (TG) in Quebec platelet disorder (QPD)-a bleeding disorder caused by a PLAU duplication mutation that increases platelet (but not plasma) urokinase plasminogen activator (uPA), leading to intraplatelet (but not systemic) plasmin generation that degrades ?-granule proteins and causes platelet (but not plasma) factor V (FV) deficiency.MethodsCalibrated automated thrombograms was used to test QPD (n = 7) and control (n = 22) PPP and PRP, with or without added tranexamic acid (TXA). TG endpoints were evaluated for relationships to platelet FV and uPA, plasma FV and tissue factor pathway inhibitor (TFPI) levels, and bleeding scores.ResultsQuebec platelet disorder PPP TG was normal whereas QPD PRP had reduced endogenous thrombin potential and peak thrombin concentrations (P values < .01), proportionate to the platelet FV deficiency (R2 ? 0.81), but unrelated to platelet uPA, plasma FV, or bleeding scores. QPD TG abnormalities were not associated with TFPI abnormalities and were not reproduced by adding uPA to control PRP. TXA increased QPD and control PRP TG more than PPP TG, but it did not fully correct QPD PRP TG abnormalities or improve TG by plasminogen-deficient plasma.ConclusionQuebec platelet disorder results in a platelet-specific TG defect, proportionate to the loss of platelet FV, that is improved but not fully corrected by TXA. Our study provides an interesting example of why it is important to assess both PRP and PPP TG in bleeding disorders.

| S-EPMC7754340 | biostudies-literature

Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions.

Project description:Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.

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Quebec platelet disorder is linked to the urokinase plasminogen activator gene (PLAU) and increases expression of the linked allele in megakaryocytes.

Project description:Quebec platelet disorder (QPD) is an autosomal dominant disorder with high penetrance that is associated with increased risks for bleeding. The hallmark of QPD is a gain-of-function defect in fibrinolysis due to increased platelet content of urokinase plasminogen activator (uPA) without systemic fibrinolysis. We hypothesized that increased expression of uPA by differentiating QPD megakaryocytes is linked to PLAU. Genetic marker analyses indicated that QPD was significantly linked to a 2-Mb region on chromosome 10q containing PLAU with a maximum multipoint logarithm of the odds (LOD) score of +11 between markers D10S1432 and D10S1136. Analysis of PLAU by sequencing and Southern blotting excluded mutations within PLAU and its known regulatory elements as the cause of QPD. Analyses of uPA mRNA indicated that QPD distinctly increased transcript levels of the linked PLAU allele with megakaryocyte differentiation. These findings implicate a mutation in an uncharacterized cis element near PLAU as the cause of QPD.

| S-EPMC2644082 | biostudies-literature

Involvement of myocyte enhancer factor 2c in the pathogenesis of autism spectrum disorder.

Project description:Myocyte enhancer factor 2 (MEF2), a family of transcription factor of MADS (minichromosome maintenance 1, agamous, deficiens and serum response factor)-box family needed in the growth and differentiation of a variety of human cells, such as neural, immune, endothelial, and muscles. As per existing literature, MEF2 transcription factors have also been associated with synaptic plasticity, the developmental mechanisms governing memory and learning, and several neurologic conditions, like autism spectrum disorders (ASDs). Recent genomic findings have ascertained a link between MEF2 defects, particularly in the MEF2C isoform and the ASD. In this review, we summarized a concise overview of the general regulation, structure and functional roles of the MEF2C transcription factor. We further outlined the potential role of MEF2C as a risk factor for various neurodevelopmental disorders, such as ASD, MEF2C Haploinsufficiency Syndrome and Fragile X syndrome.

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Rapid evolutionary rewiring of a structurally constrained eye enhancer.

Project description:BACKGROUND:Enhancers are genomic cis-regulatory sequences that integrate spatiotemporal signals to control gene expression. Enhancer activity depends on the combination of bound transcription factors as well as-in some cases-the arrangement and spacing of binding sites for these factors. Here, we examine evolutionary changes to the sequence and structure of sparkling, a Notch/EGFR/Runx-regulated enhancer that activates the dPax2 gene in cone cells of the developing Drosophila eye. RESULTS:Despite functional and structural constraints on its sequence, sparkling has undergone major reorganization in its recent evolutionary history. Our data suggest that the relative strengths of the various regulatory inputs into sparkling change rapidly over evolutionary time, such that reduced input from some factors is compensated by increased input from different regulators. These gains and losses are at least partly responsible for the changes in enhancer structure that we observe. Furthermore, stereotypical spatial relationships between certain binding sites ("grammar elements") can be identified in all sparkling orthologs-although the sites themselves are often recently derived. We also find that low binding affinity for the Notch-regulated transcription factor Su(H), a conserved property of sparkling, is required to prevent ectopic responses to Notch in noncone cells. CONCLUSIONS:Rapid DNA sequence turnover does not imply either the absence of critical cis-regulatory information or the absence of structural rules. Our findings demonstrate that even a severely constrained cis-regulatory sequence can be significantly rewired over a short evolutionary timescale.

| S-EPMC3143281 | biostudies-literature

Rewiring Host Signaling: Hepatitis C Virus in Liver Pathogenesis.

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Enhancer transcription reveals subtype-specific gene expression programs controlling breast cancer pathogenesis.

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