REGION-SPECIFIC GENE EXPRESSION AND SEX INFORM ABOUT DISEASE SUSCEPTIBILITY IN THE AORTA - MCAM Knockdown
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1242326 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Pathology in large vessels frequently develops at specific locations, implying that local stressors and spatially restricted gene expression are likely contributors to disease susceptibility. To identify site- and sex-specific differences that could inform about vulnerability, we performed single-cell transcriptomics in the carotids, aortic arch, thoracic, and abdominal aorta. Our findings revealed: (1) regionally defined transcriptional profiles, (2) signatures associated with embryonic origins, and (3) differential contributions of sex-specific effectors. Sex differences were predominantly observed in the thoracic and abdominal aorta. MCAM/CD146, a transcript with sex-skewed expression in vSMC of the abdominal aorta showed a 2.5-fold lower expression in males when compared to females. siRNA knockdown was performed to identify downstream targets of MCAM in vascular smooth muscle cells and to assess if sex affected number and biological function of genes modulated by changes in MCAM expression. MCAM was found to be further downregulated in vSMC associated with aortic aneurysms in humans. The findings reveal underlying diversity within vSMC populations with relevance to understanding site-specific and sex-specific variation of vascular pathologies.
2025-06-30 | GSE292995 | GEO
Project description:The WRAMP structure is a protein network associated with tail-end actomyosin contractility, membrane retraction, and directional persistence during cell migration. A marker of WRAMP structures is melanoma cell adhesion molecule (MCAM) which dynamically polarizes to the cell rear. However, factors that mediate MCAM polarization are still unknown. In this study, BioID using MCAM as bait identifies the ERM family proteins, moesin, ezrin, and radixin, as WRAMP structure components. We also present a novel image analysis pipeline, Protein Polarity by Percentile (“3P”), which classifies protein polarization using machine learning and facilitates quantitative analysis. Using 3P, we find that depletion of moesin, and to a lesser extent ezrin, decreases the proportion of cells with polarized MCAM. Furthermore, although co-polarized MCAM and ERM proteins show high spatial overlap, 3P identifies subpopulations with ERM proteins closer to the cell periphery. Live-cell imaging confirms that MCAM and ERM protein polarization is tightly coordinated, but ERM proteins enrich at the cell edge first. Finally, deletion of a juxtamembrane segment in MCAM previously shown to promote ERM protein interactions impedes MCAM polarization. Our findings highlight the requirement for ERM proteins in recruitment of MCAM to WRAMP structures and an advanced computational tool to characterize protein polarization.
2024-05-22 | PXD047722 | Pride
Project description:Pathologies of large vessels, such as atherosclerosis and aneurysms tend to develop at specific sites in the vascular tree. The consistency with which these events emerge suggests that a combination of unique local stressors, particularly physical forces and disturbances in gene expression profiles underlies disease etiology. We sought to investigate whether transcriptional diversity in specific segments of the aorta could be used to identify emergence of site-restricted vascular disease. Transcriptional profiling was performed using single cell RNA-seq in the carotids, aortic arch, thoracic and abdominal aorta across both sexes. Analyses of the data identified sex-invariant region-specific differences that were further validated by immunocytochemistry. Analysis of vascular smooth muscle cell transcriptomics from distinct regions of the aorta and carotids showed a high degree of similarity, but also uncovered skewed expression of a small percentage of transcripts (7.2%) towards particular vascular segments (carotid, aortic arch, thoracic and abdominal aorta). In silico cross-reference of genes known to be associated with vascular disease with the unique transcriptional signatures validated our proposed hypothesis. Specifically, we found correlations between localized-diseased causing GWAS candidate genes and region-enriched signatures. Pair-wise comparison between anatomic regions across sexes identified regional sex-specific gene signatures highlighting prominent regional-sex dependent differences were observed in vSMCs of the thoracic and abdominal aorta, consistent with sex-specific burden of aneurysm in these regions. Of these regional sex-enriched candidates’, Mcam/CD146, showed ventral thoraco-abdominal distribution, enriched expression in females and it was significantly reduced in the AngII / hypercholesterolemic model of aortic aneurysm. Furthermore, induction of aneurysms in mice lacking Mcam/CD146 resulted in larger lesions and accelerated death due to dissection.
2025-06-30 | GSE255696 | GEO
Project description:To investigate effect of Mcam KD on tumor gene expression profile in orthotopic Py230 derived grafted tumors
2024-04-10 | GSE233090 | GEO
Project description:Ewing Sarcoma is the second most common solid pediatric malignant neoplasm of the bone and soft tissue. Driven by EWS/Ets, or rarely variant, oncogenic fusions, Ewing Sarcoma is a biologically and clinically aggressive disease with a high propensity for metastasis. Our laboratory has previously identified the Jumonji-domain H3K9 me 1/2 histone demethylase KDM3A as a novel oncogene downstream of EWS/Fli1, the most common oncofusion in Ewing Sarcoma. Herein, we uncover a role for KDM3A in the promotion of Ewing Sarcoma metastasis. Using global gene expression profiling, we show that some of the most strongly regulated genes by KDM3A are those implicated in cell migration and metastasis, and demonstrate, using functional assays, that KDM3A promotes migration in vitro and metastasis in vivo. We further provide evidence that MCAM, one of the most strongly and consistently regulated genes by KDM3A, is an important effector of KDM3A pro-metastatic action. Our studies also show that KDM3A regulates MCAM expression both through a direct mechanism, involving modulation of H3K9 methylation at the MCAM promoter, and an indirect mechanism, via the Ets1 transcription factor.
2017-02-08 | GSE94619 | GEO
Project description:The aim of this experiment was to investigate cellular heterogeneity of VE-Cadherin+ cells isolated from mouse E10.5 aorta-gonad-mesonephros region.
2019-03-12 | E-MTAB-6987 | biostudies-arrayexpress
Project description:Pediatric patients with recurrent metastatic Ewing sarcoma (ES) have a dismal 5-year survival of < 30% largely secondary to treatment resistance in the tumor microenvironment (TME). Novel therapeutic approaches are desperately needed and represent an unmet need. Here, we developed a chimeric antigen receptor (CAR) expressing natural killer (NK) cell targeting melanoma cell adhesion molecule (MCAM) by electroporation of CAR mRNA into ex-vivo expanded NK cells. Expression of anti-MCAM CAR significantly and specifically enhanced NK cytotoxic activity compared to mock NK cells against MCAMhigh ES cells in vitro, and significantly reduced lung metastasis and extended animal survival in an orthotopic xenograft mouse model of ES. However, anti-MCAM CAR NK cells had minimal effects on decreasing primary tumor growth in vivo. We performed transcriptome profiling in patient-derived xenografts to identify the underlying mechanisms of NK cell resistance in ES TME.
2024-09-18 | GSE251936 | GEO
Project description:The aim of the experiment was to compare newly defined CD44Neg, CD44LoKitNeg, CD44LoKitPos and CD44High populations from mouse Aorta-Gonad-Mesonephros (AGM) region
2019-03-29 | GSE128971 | GEO
Project description:Haematopoietic stem cells (HSCs) first emerge in the embryonic aorta-gonad-mesonephros (AGM) region. Studies on model organisms defined intersecting signalling pathways that converge to promote HSC emergence predominantly in the ventral domain of the dorsal aorta. Much less is known about mechanisms driving HSC development in human. Here, to identify secreted signals underlying human HSC development, we combined spatial transcriptomics analysis of dorso-ventral polarised signalling in the aorta with gene expression profiling of sorted cell populations and single cells. Our analysis revealed a subset of aortic endothelial cells with downregulated arterial signature and a predicted lineage relationship with the emerging HSC/ progenitor population. Analysis of the ventrally polarised molecular landscape identified endothelin 1 as an important secreted regulator of human HSC development. The obtained gene expression datasets will inform future studies on mechanisms of HSC development in vivo and on the generation of clinically relevant HSCs in vitro.
2020-09-17 | GSE151877 | GEO