POSITIONAL TRANSCRIPTOMICS SHED LIGHT ON SITE-SPECIFIC PATHOLOGIES OF THE AORTA
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PROVIDER: PRJNA1076177 | ENA |
REPOSITORIES: ENA
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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:scRNA-seq of male mouse aorta collected over the light-dark cycle
2022-09-13 | GSE206583 | GEO
Project description:PurposePlasmalogens (Plgs) are highly abundant lipids in the retina, and their deficiency leads to severe abnormalities during eye development. The first acylation step in the synthesis of Plgs is catalyzed by the enzyme glyceronephosphate O-acyltransferase (GNPAT), which is also known as dihydroxyacetone phosphate-acyltransferase (EC 2.3.1.42). GNPAT deficiency produces rhizomelic chondrodysplasia punctata type 2, a genetic disorder associated with developmental ocular defects. Despite the relevance of retinal Plgs, our knowledge of the mechanisms that regulate their synthesis, and the role of GNPAT during eye development is limited.MethodsUsing the Xenopus laevis model organism, we characterized by in situ hybridization the expression pattern of gnpat and compared it to glycerol 3-phosphate acyltransferase mitochondrial (gpam or gpat1) during eye neurogenesis, lamination, and morphogenesis. The Xenopus Gnpat was biochemically characterized in a heterologous expression system in yeast.ResultsDuring development, gnpat is expressed in proliferative cells of the retina and lens, and post-embryogenesis in proliferative cells of the ciliary marginal zone and lens epithelium. In contrast, gpam expression is mainly restricted to photoreceptors. Xenopus Gnpat expressed in yeast is present in both soluble and membrane fractions, but only the membrane-bound enzyme displays activity. The amino terminal of Gnpat, conserved in humans, shows lipid binding capacity that is enhanced by phosphatidic acid.ConclusionsEnzymes involved in the Plgs and glycerophospholipid biosynthetic pathways are differentially expressed during eye morphogenesis. The gnpat expression pattern and the molecular determinants regulating Gnpat activity advance our knowledge of this enzyme, contributing to our understanding of the retinal pathophysiology associated with GNPAT deficiency.
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Project description:Profiling of chromosomal gains and losses in a genomic complement of stem cells from human exfoliated deciduous teeth comparing control undifferentieated SHED with hepatocyte differentiated SHED.
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Project description:Amputation of a salamander limb triggers anterior and posterior connective tissue cells to form distinct signalling centres that together fuel regeneration. Anterior and posterior identities are established during development and are thought to persist lifelong in the form of positional memory. However, neither the molecular basis of positional memory nor whether positional memory can be altered is known. Here, we identify a positive feedback loop responsible for posterior identity in the axolotl (Ambystoma mexicanum) limb. Posterior cells express residual Hand2 transcription factor from development, which primes them to form a Shh signalling centre after limb amputation. During regeneration, Shh signalling is also upstream of Hand2 expression. After regeneration, Shh is shut down but Hand2 is sustained, safeguarding posterior memory. We exploited this regeneration circuitry to convert anterior cells to a posterior cell memory state. Transient exposure of anterior cells to Shh during regeneration kick-started an ectopic Hand2-Shh loop, leading to stable Hand2 expression and a lasting competence to express Shh. Our results implicate positive feedback in the stability of positional memory and reveal that positional memory is more easily reprogrammed in one direction (anterior to posterior) than the other. Modifying positional memory in regenerative cells changes their signalling outputs, which has implications for tissue engineering.
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Project description:Amputation of a salamander limb triggers anterior and posterior connective tissue cells to form distinct signalling centres that together fuel regeneration. Anterior and posterior identities are established during development and are thought to persist lifelong in the form of positional memory. However, neither the molecular basis of positional memory nor whether positional memory can be altered is known. Here, we identify a positive feedback loop responsible for posterior identity in the axolotl (Ambystoma mexicanum) limb. Posterior cells express residual Hand2 transcription factor from development, which primes them to form a Shh signalling centre after limb amputation. During regeneration, Shh signalling is also upstream of Hand2 expression. After regeneration, Shh is shut down but Hand2 is sustained, safeguarding posterior memory. We exploited this regeneration circuitry to convert anterior cells to a posterior cell memory state. Transient exposure of anterior cells to Shh during regeneration kick-started an ectopic Hand2-Shh loop, leading to stable Hand2 expression and a lasting competence to express Shh. Our results implicate positive feedback in the stability of positional memory and reveal that positional memory is more easily reprogrammed in one direction (anterior to posterior) than the other. Modifying positional memory in regenerative cells changes their signalling outputs, which has implications for tissue engineering.
2025-03-21 | GSE284768 | GEO
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.
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Project description:Identify genes in the aorta whose expressions under genetic regulation in the Hybrid Mouse Diversity Panel (HMDP). The HDMP is comprised of classical inbred and recombinant inbred wild-type mice. The RMA values of genes were used for genome-wide association as described in Bennett et al. Genome Research 2010 (PMID 20054062). These data were used to identify candidate genes at loci associated with atherosclerosis. Genome-wide association study (GWAS) for expression in aorta of inbred strains.
2012-11-18 | E-GEOD-38120 | biostudies-arrayexpress
Project description:Data set to accompany : Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet. 2006 Jul;2(7):e119. PMID: 16895450 Fibroblasts are ubiquitous mesenchymal cells with many vital functions during development, tissue repair, and disease. Fibroblasts from different anatomic sites have distinct and characteristic gene expression patterns, but the principles that govern their molecular specialization are poorly understood. Spatial organization of cellular differentiation may be achieved by unique specification of each cell type; alternatively, organization may arise by cells interpreting their position along a coordinate system. Here we test these models by analyzing the genome-wide gene expression profiles of primary fibroblast populations from 43 unique anatomical sites spanning the human body. Large-scale differences in the gene expression programs were related to three anatomic divisions: anterior-posterior (rostral-caudal), proximal-distal, and dermal versus nondermal. A set of 337 genes that varied according to these positional divisions was able to group all 47 samples by their anatomic sites of origin. Genes involved in pattern formation, cell-cell signaling, and matrix remodeling were enriched among this minimal set of positional identifier genes. Many important features of the embryonic pattern of HOX gene expression were retained in fibroblasts and were confirmed both in vitro and in vivo. Together, these findings suggest that site-specific variations in fibroblast gene expression programs are not idiosyncratic but rather are systematically related to their positional identities relative to major anatomic axes. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Computed
2010-07-01 | E-GEOD-5591 | biostudies-arrayexpress