Gene expression profile in platelets of mouse regulated by Smad4 gene
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE43814 | GEO | 2013/01/29
SECONDARY ACCESSION(S): PRJNA187493
REPOSITORIES: GEO
Similar Datasets
Project description:Mutations of SMAD family member 4 (Smad4) gene caused Hereditary Hemorrhagic Telangiectasia (HHT). It was believed that bleeding disorders were caused by arteriovenous malformation in this syndrome. Although several studies indicated dysfunction of platelets from HHT patient, the role(s) of smad4 in platelet function has not been examined. In this study, using megakaryocyte/platelet-specific Smad4-deficient mice, we investigated the physiological function of Smad4 in platelet activation and the underlying mechanism. Microarray data demonstrated that the level of mRNA for multiple genes changed in Smad4 deficient platelet. For microarray analysis, total mRNA was extracted from washed platelets from Smad4f/f or Smad4M-bM-^HM-^R/M-bM-^HM-^R mice (for each group, n=6). mRNA was labeled and hybridized to Affymetrix Mouse Genome 430 2.0 chips according to manufacturer's instructions (Affymetrix).
2013-01-29 | E-GEOD-43814 | biostudies-arrayexpress
Project description:Purpose: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by arteriovenous malformations (AVMs). Over 90% of HHT patients carry heterozygous loss-of-function mutations in Transforming Growth Factor-beta (TGFb) signaling components activin receptor-like kinase 1 (ACVRL1/ALK1), endoglin (ENG), or mothers against decapentaplegic homolog 4 (SMAD4). Brain AVMs can be lethal for HHT patients. Here, we use an inducible endothelial (EC)-specific mouse line to investigate brain AVMs characteristics in Alk1-, Eng-, and Smad4-HHT mouse models. Angiopientin-2 (Ang2) inhibition diminishes HHT associated cerebral vascular defects. We aim to identify the shared transcriptional changes in brain ECs between these three HHT types, and provide insights for transcriptional changes upon Ang2 inhibition. Methods: ECs were isolated from brains of both WT and HHT mutant mice at postnatal day 7 (P7) for Smad4 and Eng models, P6 for Alk1 model. Total RNA was extracted from isolated brain ECs and quantified using Qubit RNA High Sensitivity Assay Kit. RNA integrity was determined using the Bioanalyzer RNA 6000 Nano assay kit. RNA library construction was performed with the TruSeq RNA Library Prep Kit v2 from Illumina. The resulting mRNA library was quantified using Qubit dsDNA High Sensitivity Assay Kit and verified using the Bioanalyzer DNA1000 assay kit. Verified samples were sequenced using the NextSeq 500/550 High Output Kit v2.5 (150 Cycles) on a Nextseq 550 system. Sequenced reads were aligned to the mouse (mm10) reference genome with RNA-seq alignment tool (version 2.0.1). The aligned reads were used to quantify mRNA expression and determine differentially expressed genes using the RNA-seq Differential Expression tool (version 1.0.1). Both alignment and differential expression analysis were performed using the tools in the BaseSpace Sequence Hub. Results: We identified 5509, 5381, and 2663 differentially expressed genes in Smad4, Alk1, and Eng HHT models respectively. Also, Ang2 inhibition mainly funcioned through angiogenesis and cell migration processes to normalize cerebrovascular defects in Smad4-HHT model. Conclusions: A common but unique pro-angiogenic program among all HHT models included 14 consistent upregulated and 5 consistent downregulated angiogic genes. Also, Ang2 inhibition mainly funcioned through angiogenesis and cell migration processes to normalize cerebrovascular defects in Smad4-HHT model.
2023-05-19 | GSE197105 | GEO
Project description:Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominantly inherited vascular disease characterized by the presence of mucocutaneous telangiectasia and arteriovenous malformations in visceral organs. HHT is predominantly caused by mutations in ENG and ACVRL1, Which both belong to the TGF-M-NM-2 signalling pathway. Further knowledge on how a disturbance of the TGF-M-NM-2 signalling pathway leads to HHT manifestations is needed in order to identify potential therapeutic targets. As long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression and constitute a sizable fraction of the human transcriptome, we wanted to assess whether lncRNAs play a role in the molecular pathogenesis of HHT. Here we used microarray analysis to profile lncRNAs to compare the expression of HHT telangiectasial and HHT non-telangiectasial nasal tissue from the same patient in a paired design. The microarray probes were re-annotated using the GENCODE v.16 dataset, identifying 4,810 probes mapping to 2,811 lncRNAs. By comparing HHT telangiectasial tissue versus HHT non-telangiectasial tissue, we identified 42 lncRNAs that are differentially expressed (q<0.001). Using GREAT, a tool that assumes cis-regulation, we showed that differently expressed lncRNAs are enriched for genomic loci involved in key pathways concerning HHT. Our study identified lncRNAs that are aberrantly expressed in HHT telangiectasia and indicates that lncRNAs may contribute to regulate protein-coding loci in HHT. Which suggest that the lncRNA component of the transcriptome deserves more attention in HHT. A deeper understanding of lncRNAs and their role in telangiectasia formation possesses potential for discovering therapeutic targets in HHT. Gene expression profiling of 80 paired nasal samples from patients with hereditary Haemorrhagic Telangiectasia (HHT), representing telangiectasial and non-telangiectasial (normal) tissue respectively. The patients were divided into HHT1 or HHT2 in regard to the germline mutation in ENG (HHT1) or ACVRL1 (HHT2). Additional controls were healthy siblings (not carrying the germline mutation) and external controls. The study was conducted using Agilent-028004 SurePrint G3 Human GE 8x60K Microarray platform.
2014-12-19 | E-GEOD-53515 | biostudies-arrayexpress
Project description:Vascular networks form, remodel and mature under the influence of both fluid shear stress (FSS) and soluble factors. Physiological FSS promotes and maintains vascular stability via synergy with Bone Morphogenic Protein 9 (BMP9) and BMP10. Conversely, mutation of the BMP receptors ALK1, Endoglin or the downstream effector SMAD4 leads to Hereditary Hemorrhagic Telangiectasia (HHT), characterized by fragile and leaky arterial-venous malformations (AVMs). But how endothelial cells (EC) integrate FSS and BMP signals in vascular development and homeostasis, and how mutations give rise to vascular malformations is not well understood. Here, we aimed to elucidate the mechanism of synergy between fluid shear stress and SMAD signaling in vascular stability and its failure in HHT. We have now found that loss of Smad4 increases ECs’ sensitivity to flow by lowering the FSS set point with resulting AVMs exhibiting features of excessive flow-mediated morphological responses. Mechanistically, loss of Smad4 disinhibits flow-mediated Klf4-Tie2-PI3K/Akt signaling leading to increased EC proliferation and loss of arterial identity due to Klf4-mediated repression of cyclin dependent Kinase (CDK) inhibitors, CDKN2A and CDKN2B. Thus, AVMs caused by Smad4 deletion are characterized by chronic high flow remodeling with excessive EC proliferation and loss of arterial identity as triggering events.
2023-07-03 | GSE232443 | GEO
Project description:Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominantly inherited vascular disease characterized by the presence of mucocutaneous telangiectasia and arteriovenous malformations in visceral organs. HHT is predominantly caused by mutations in ENG and ACVRL1, Which both belong to the TGF-β signalling pathway. Further knowledge on how a disturbance of the TGF-β signalling pathway leads to HHT manifestations is needed in order to identify potential therapeutic targets. As long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression and constitute a sizable fraction of the human transcriptome, we wanted to assess whether lncRNAs play a role in the molecular pathogenesis of HHT. Here we used microarray analysis to profile lncRNAs to compare the expression of HHT telangiectasial and HHT non-telangiectasial nasal tissue from the same patient in a paired design. The microarray probes were re-annotated using the GENCODE v.16 dataset, identifying 4,810 probes mapping to 2,811 lncRNAs. By comparing HHT telangiectasial tissue versus HHT non-telangiectasial tissue, we identified 42 lncRNAs that are differentially expressed (q<0.001). Using GREAT, a tool that assumes cis-regulation, we showed that differently expressed lncRNAs are enriched for genomic loci involved in key pathways concerning HHT. Our study identified lncRNAs that are aberrantly expressed in HHT telangiectasia and indicates that lncRNAs may contribute to regulate protein-coding loci in HHT. Which suggest that the lncRNA component of the transcriptome deserves more attention in HHT. A deeper understanding of lncRNAs and their role in telangiectasia formation possesses potential for discovering therapeutic targets in HHT.
2014-12-19 | GSE53515 | GEO
Project description:Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations focally develop in multiple organs. These can be small (telangiectasias) or large (arteriovenous malformations, AVMs) and can compromise tissue perfusion. Critically, they are prone to rupture leading to frequent and uncontrolled bleeding. As a result, HHT patients experience several debilitating clinical manifestations that reduce patient quality-of-life. Most HHT patients are heterozygous for loss-of-function mutations affecting signaling through the Alk1 pathway; yet, the pathogenesis of vascular malformation (VM) in HHT patients remains unclear and there are still few treatment options and no cure. Due to the complex, three-dimensional, and multicellular nature of vascular lesions in HHT, they are traditionally studied in intact genetically-modified mouse and zebrafish models, and studies in these animals have yielded important insights into HHT disease progression. However, intact animal studies can be time-consuming and expensive, and may be difficult to translate to human patients. In this study, we take advantage of our recently developed Vascularized Micro-Organ platform to develop an in vitro fully-humanized HHT-on-a-chip microphysiological model (HHT-VMO) that recapitulates vascular lesions of HHT patients. Using a tunable IPTG-inducible ACVRL1 (Alk1)-knockdown approach, we control the timing and extent of endogenous Alk1 expression in primary human endothelial cells seeded into the HHT-VMO device. We report that Alk1-deficient EC reliably form networks with aberrant morphology that includes lesions reminiscent of both patient telangiectasias and AVMs. HHT-VMO lesions are dependent upon the timing of Alk1 knockdown and their formation is blocked by the Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitor pazopanib. Lastly, we find that AVM-like lesions that form in the HHT-VMO are comprised of mixed Alk1-intact and Alk1-deficient EC suggesting cell non-autonomous effects. Taken together, we report development of a novel HHT-on-a-chip model that appears to faithfully reproduce HHT patient lesions. In the future, we hope to use this model to better understand HHT disease biology and to perform drug screening studies to identify a cure for HHT.
2024-07-31 | GSE252666 | GEO
Project description:Patients with a heterozygous mutation in Endoglin (Eng) suffer from hereditary hemorrhagic telangiectasia (HHT), a condition characterized by the development of arteriovenous malformations (AVMs) across various organs, leading to significant bleeding, blood abnormalities, and anemia. Eng is a transmembrane protein and an accessory receptor for transforming growth factor-β (TGF-β) and is therefore essential for maintaining normal vascular architecture. Despite extensive research linking Eng deficiency to AVMs, the precise mechanisms driving this association remain poorly understood. In addition, the role of the bone marrow, a primary source of immune and other blood cells, in the context of endothelial Eng (EC-Eng) deficiency has yet to be explored. In this study, we demonstrate that bone marrow blood vessels conditionally deficient in Eng undergo a temporally orchestrated remodeling process over four weeks, characterized by distinct proliferative and resolution phases. We detail the specific phases of this remodeling, including angiogenic set points, the involvement of the beta integrin family, and modulation of vascular integrity. Furthermore, we explore the impact on the hematopoietic stem and progenitor cell (HSPC) compartment and the resultant changes in circulating blood cells. Using a conditional heterozygous deficient EC-Eng mouse model, we observe significant similarities to phenotypes described in the cKO line, which may ultimately be detrimental in patients with HHT. Taken together, using a combination of different in vivo approaches, our research proposes that very low levels of Eng expression in the endothelium may drive critical vascular remodeling in the bone marrow, sharing mechanisms with early vascular processes leading to AVM formation.
2024-07-25 | GSE271409 | GEO
Project description:Distinct endothelial cell cycle states (early G1 vs. late G1) provide different “windows of opportunity” to enable the differential expression of genes that regulate venous and arterial specification, respectively. Endothelial cell cycle control and arterial-venous identities are disrupted in vascular malformations including arteriovenous (AV) shunts which is a hallmark of hereditary hemorrhagic telangiectasia (HHT). We show how endothelial cell late G1 arrest induced by Palbociclib modulates the expression of genes regulating arterio-venous identity and prevents AVM development induced by BMP9/10 inhibition.
2023-12-31 | GSE245197 | GEO
Project description:Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular dysplasia characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM) in visceral organs. In this study, we carried out a liquid biopsy consisting in the isolation of total RNA from plasma exosomes samples from HHT type 1 (HHT1 group) and type 2 (HHT2 group) patients, and healthy relatives (Control group). Upon gene expression data processing and normalization, a bioinformatics analysis was performed for the study of principal components, hierarchical clustering and pairwise comparisons between HHT samples and control group. Results were evaluated in a further validation cohort of HHT and healthy donors by real time PCR and the diagnosis value of exosomal miRNA determined by the ROC curves analysis. We found that exosomal miRNA expression signature clearly distinguishes among healthy and HHT samples and types. Thus, we identified a disease-associated molecular fingerprint of 35 miRNAs over-represented, being 8 specifics for HHT1 and 11 for HHT2; and 30 under-represented, including 9 distinctive for HHT1 and 9 for HHT2. These exosome-transported miRNAs have diagnosis value for HHT, and even allow to distinguish between HHT1 and HHT2.
2021-09-28 | GSE179382 | GEO
Project description:Understanding the underlying mechanisms of the well-established platelet hyporeactivity in neonates, would be of great relevance for both improving the clinical management of neonates, a population with a higher bleeding risk than adults (especially among sick and preterm infants), and getting new insights onto the regulatory mechanisms of platelet biology. Transcriptome analysis is a useful tool to identify mRNA signature affecting platelet function. However, human fetal/neonatal platelet transcriptome analysis has never been reported. Here, we used, for the first time, mRNA expression array to compare the platelet transcriptome changes during development. Microarray analysis was performed in pure platelet RNA obtained from adult and cord blood, using the same platform in two independent laboratories. A high correlation was obtained between arrays results for both adult and neonate platelet samples. There was also a good agreement between our adult results and those previously reported in three different studies. Gene enrichment analysis demonstrated that immunity- and platelet function-related genes are highly expressed in either developmental stage. Remarkably, 201 genes were found to be differentially expressed along development. In particular, neonatal platelets contain higher levels of mRNA that are associated with protein synthesis and processing, while they carry significantly lower levels of genes related with calcium transport/metabolism and cell signaling (including GNAZ). Overall, our results highlight that variations in platelet transcriptome may underline the hypo-functional phenotype of neonatal platelets, and further support the role of platelets in cellular immune response. A better characterization of the platelet transcriptome across development may help to elucidate the implications of transcriptome changes in different pathological conditions.
2017-02-03 | GSE94292 | GEO