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PubMed2026

An integrated single-cell and spatial transcriptomic atlas of thyroid cancer progression identifies prognostic fibroblast subpopulations.

Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts (myCAFs) that are intimately associated with invasive tumor cells and correlate with poor prognosis, lymph node metastasis, and disease progression in thyroid carcinoma. We also revealed a population of inflammatory CAFs that are distant to tumor cells and are found in the inflammatory stromal microenvironment of autoimmune thyroiditis. Together, our study provides spatial profiling of thyroid cancer evolution in samples with mixed WDTC/ATC histopathology and identifies a prognostic myCAF subtype with potential clinical utility in predicting aggressive disease in both children and adults.

Humans↗
PubMed2006

Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription.

Cannabis use in pregnancy is associated with a range of obstetrical conditions. The molecular mechanisms underlying these effects have not been elucidated but are attributed to the actions of delta-9-tetrahydrocannabinol (Delta9-THC). In this study, concentrations of Delta9-THC equivalent to those found in the serum of cannabis users, i.e. approximately 20 microM, inhibited proliferation and activated a restricted tight transcriptional programme in the BeWo trophoblast cell line. Employing genome-wide expression profiling methods, we found that the pattern of gene expression differs from that described in the placenta of patients with fetal growth restriction (FGR), associated with either hypoxia or discordant dichorionic twins, or of patients with pre-eclampsia. It was also dissimilar to the patterns obtained from the transcriptome of other tissues, such as the mouse brain, treated with Delta9-THC. The expression of transcription factors, such as thyroid hormone receptor-beta1 (TRbeta1), and transcriptional co-repressors, such as histone deactylase 3 (HDAC3), was affected by Delta9-THC in a dose-dependent manner, whereby 15 microM Delta9-THC caused a 2.8-fold inhibition of TRbeta1 expression, but a 3.5-fold increase in HDAC3 expression. These data were confirmed by end-point RT-PCR analyses and underpin the observed Delta9-THC-induced inhibition of BeWo cell proliferation. Genes encoding for growth, apoptosis, cell morphology and ion exchange pathways were modulated by 15 microM Delta9-THC. This study may provide insight into the mechanisms underlying the effects of Delta9-THC and cannabis use upon placental development during pregnancy.

Analgesics, Non-Narcotic↗
PubMed2004

Kinetic analysis of cardiac transcriptome regulation during chronic high-fat diet in dogs.

In the present study, we investigated, using custom dog cDNA arrays, the time course of transcriptional changes in the left ventricle of dogs fed a normal diet or a high-fat diet (HFD) for 9-24 wk. Array hybridizations were performed with complex probes representing mRNAs expressed in left ventricles from obese hypertensive and lean control dogs. We identified 63 differentially expressed genes, and expression of 17 of 20 randomly chosen genes was confirmed by real-time PCR. Transcripts were categorized into groups involved in metabolism, cell signaling, tissue remodeling, ionic regulation, cell proliferation, and protein synthesis. Hierarchical clustering indicated that the pattern of coregulated genes depends on duration of the HFD, suggesting that HFD-induced obesity hypertension is associated with continuous cardiac transcriptome adaptation despite stability of both body weight and blood pressure. GenMAPP analysis of the data pointed out the crucial importance of the ventricle TGF-beta pathway. Our results suggest that this system may be involved in molecular remodeling during HFD and in changes observed in the transcription profile, reflecting functional and morphological abnormalities that arise during prolonged HFD. These results also suggest some novel regulatory pathways for cardiac adaptation to obesity.

Animals↗
PubMed2005

A proteomic analysis of mammalian preimplantation embryonic development.

Genetic studies on the mammalian preimplantation embryo are providing a wealth of information regarding gene expression. However, changes in the transcriptome do not always reflect cellular function or the complexity and diversity of the mammalian proteome with post-translational modifications or protein-protein interactions. To elucidate embryonic cellular function, a detailed understanding at the protein level is necessary. The aim of this study was to generate protein profiles of mammalian embryos throughout development, and to investigate the effects of oxygen concentration on the embryonic proteome. A protocol was developed to analyse small groups of embryos (n = 5) by time-of-flight mass spectrometry. F1 mice zygotes were cultured in G1/G2 sequential media with recombinant albumin (2.5 mg/ml) in 6% CO(2) and O(2) concentrations of either 5% or 20%. In vivo-developed embryos were flushed from the reproductive tract (day 4). Protein profiles were generated for all embryonic samples and statistical analysis revealed 32 potential proteins/biomarkers with significant changes (P < 0.05). Embryos generated under 5% O(2) more closely resembled in vivo-developed embryos. Under 20% O(2) conditions, embryos showed down-regulation of 10 proteins/biomarkers (masses between 4 to 20 kDa) (P < 0.05) confirming the pathological effects of oxygen during embryonic development. These data demonstrate for the first time the complexity of the mammalian preimplantation proteome. The unique protein profiles of in vivo-developed embryos and a panel of selected biomarkers represent optimal cellular function, against which comparisons can be made to facilitate improvements in mammalian assisted reproduction techniques procedures.

Animals↗
PubMed2005

Ethical and legal aspects of applied genomic technologies: practical solutions.

Many ethical and legal issues surround genomic technologies, some of which are present for other kinds of medical data, but some of which are specific to genomic data. Specifically the global nature of genomic data and the life-long implications of genetic defects on the health of the individual subject produce challenges in the ethical and legal handling of this data. In general, data derived from transcriptome analysis, which studies gene expression, as well as proteomics and metabolomics, carry less ethically-charged information than measures of the germ line genome. However, theoretical issues that have been raised related to withholding therapy based on a specific genotype which could also apply to a specific expression profile. Potential solutions for these challenges are discussed, such as maintaining a connection with research participants through a trusted third party, using electronic means to manage that contact and reconsent subjects. A flexible, secure information technology infrastructure is proposed to manage and search consent forms, provide the ability to collect additional data and consent while maintaining participant confidentiality.

Access to Information↗
PubMed2006

Genome-wide expression profile of the mnn2 Delta mutant of Saccharomyces cerevisiae.

The MNN2 gene of S. cerevisiae encodes an alpha (1,2) mannosyl transferase required for branching the outer chain of N-linked oligosaccharides (Rayner J.C. and Munro S. 1998. J. Biol. Chem. 273: 26836-26843) and it also seems to have some effect on the transfer of mannosyl phosphate groups to the inner core (Olivero I. et al. 2000. FEBS Lett. 475: 111-116). In order to reveal possible interactions of MNN2 expression with other cellular pathways, we analyzed the transcriptome of the deletion mutant S. cerevisiae mnn2 Delta using cDNA microarrays. We found 151 genes that showed an altered expression level of > or =2-fold, 58 of them up-regulated and 93 down-regulated. Quite a high proportion of these genes (29%) encode unclassified proteins. In contrast to other defects affecting the integrity of the cell wall, deletion of MNN2 does not stimulate the expression of any of the genes included in the previously defined 'cell wall compensatory cluster' (Lagorce et al. 2003. J. Biol. Chem. 278: 20345-20357). We also found that 15% of the selected genes are related to central metabolic pathways. In addition, the mnn2 Delta strain seems to have a certain level of stimulation of DNA processing reactions while some genes involved in intracellular transport pathways are under-regulated.

Gene Deletion↗
PubMed2005

Human muscle gene expression responses to endurance training provide a novel perspective on Duchenne muscular dystrophy.

Global gene expression profiling is used to generate novel insight into a variety of disease states. Such studies yield a bewildering number of data points, making it a challenge to validate which genes specifically contribute to a disease phenotype. Aerobic exercise training represents a plausible model for identification of molecular mechanisms that cause metabolic-related changes in human skeletal muscle. We carried out the first transcriptome-wide characterization of human skeletal muscle responses to 6 wk of supervised aerobic exercise training in 8 sedentary volunteers. Biopsy samples before and after training allowed us to identify approximately 470 differentially regulated genes using the Affymetrix U95 platform (80 individual hybridization steps). Gene ontology analysis indicated that extracellular matrix and calcium binding gene families were most up-regulated after training. An electronic reanalysis of a Duchenne muscular dystrophy (DMD) transcript expression dataset allowed us to identify approximately 90 genes modulated in a nearly identical fashion to that observed in the endurance exercise dataset. Trophoblast noncoding RNA, an interfering RNA species, was the singular exception-being up-regulated by exercise and down-regulated in DMD. The common overlap between gene expression datasets may be explained by enhanced alpha7beta1 integrin signaling, and specific genes in this signaling pathway were up-regulated in both datasets. In contrast to these common features, OXPHOS gene expression is subdued in DMD yet elevated by exercise, indicating that more than one major mechanism must exist in human skeletal muscle to sense activity and therefore regulate gene expression. Exercise training modulated diabetes-related genes, suggesting our dataset may contain additional and novel gene expression changes relevant for the anti-diabetic properties of exercise. In conclusion, gene expression profiling after endurance exercise training identified a range of processes responsible for the physiological remodeling of human skeletal muscle tissue, many of which were similarly regulated in DMD. Furthermore, our analysis demonstrates that numerous genes previously suggested as being important for the DMD disease phenotype may principally reflect compensatory integrin signaling.

Biopsy↗
PubMed2007

Laser-assisted microdissection (LAM) in developmental biology.

The analysis of gene expression in developing organs is a valuable tool for the assessment of genetic fingerprints during the various stages of differentiation. Complex processes in developing tissues are particularly difficult to understand in terms of biochemical phenomena. Laser-assisted microdissection (LAM) allows the efficient and precise capture of cells or groups of cells from developing tissues in sufficient quantities and within the context of time and space to permit the subsequent molecular characterization of the targeted tissue. The technique development has dramatically increased the ease of isolating specific cells which, together with progress in tissue preparation and microextraction protocols, allows for broad-range down-stream applications in the fields of genomics, transcriptomics and proteomics. This review gives an overview of the LAM technology and its application in developmental biology.

Animals↗
PubMed2006

Methods and platforms for the quantification of splice variants' expression.

The relatively limited number of human protein encoding genes highlights the importance of the diversity generated at the level of the mRNA transcripts. As alternative RNA splicing plays a key role in mediating this diversity, it becomes critical to develop the tools and platforms that will deliver quantitative information on the specific expression levels associated with splice isoforms. This chapter describes the constraints generated by this global transcriptome analysis and the state-of-the-art techniques and products available to the scientific community.

Alternative Splicing↗
PubMed2005

A genome-wide analysis of the effects of sucrose on gene expression in Arabidopsis seedlings under anoxia.

Exogenous sucrose (Suc) greatly enhances anoxia tolerance of Arabidopsis (Arabidopsis thaliana) seedlings. We used the Affymetrix ATH1 GeneChip containing more than 22,500 probe sets to explore the anaerobic transcriptome of Arabidopsis seedlings kept under anoxia for 6 h in presence or absence of exogenous Suc. Functional clustering was performed using the MapMan software. Besides the expected induction of genes encoding enzymes involved in Suc metabolism and alcoholic fermentation, a large number of genes not related to these pathways were affected by anoxia. Addition of exogenous Suc mitigated the effects of anoxia on auxin responsive genes that are repressed under oxygen deprivation. Anoxia-induced Suc synthases showed a lower induction in presence of exogenous Suc, suggesting that induction of these genes might be related to an anoxia-dependent sugar starvation. Anoxic induction of genes coding for heat shock proteins was much stronger in presence of exogenous Suc. Interestingly, a short heat treatment enhanced anoxia tolerance, suggesting that heat shock proteins may play a role in survival to low oxygen. These results provide insight into the effects of Suc on the anoxic transcriptome and provide a list of candidate genes that enhance anoxia tolerance of Suc-treated seedlings.

Anaerobiosis↗
PubMed2006

Analysis of SAGE data in human platelets: features of the transcriptome in an anucleate cell.

A comprehensive SAGE (serial analysis of gene expression) library of purified human platelets was established. Twenty-five thousand (25,000) tags were sequenced, and after removal of mitochondrial tags, 12,609 (51%) non-mitochondrial-derived tags remained, corresponding to 2,300 different transcripts with expression levels of up to 30,000 tags per million. This new, highly purified SAGE library of platelets is enriched in specific transcripts. The complexity in terms of tag distribution is similar to cells that are still able to replenish their mRNA pool by transcription. We show that our SAGE data are consistent with recently published microarray data but show further details of the platelet transcriptome, including (i) longer UTR regions and more stable folding in the enriched mRNAs, (ii) biologically interesting new candidate mRNAs that show regulatory elements, including elements for RNA stabilization or for translational control, and (iii) significant enrichment of specific, highly transcribed mRNAs compared to a battery of SAGE libraries from other tissues. Among several regulatory mRNA elements known to be involved in mRNA localization and translational control, CPE elements are in particular enriched in the platelet transcriptome. mRNAs previously reported to be translationally regulated were found to be present in the library and were validated by real-time PCR. Furthermore, specific molecular functions such as signal transduction activity were found to be significantly enriched in the platelet transcriptome. These findings emphasize the richness and diversity of the platelet transcriptome.

3' Untranslated Regions↗
PubMed2025

Comprehensive proteomic and pathological profiling identifies PRAS40 as a novel biomarker and mediator of primary immune checkpoint blockade resistance in non-small cell lung cancer.

BACKGROUND: Immune checkpoint blockade (ICB) has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), yet primary resistance remains a significant clinical challenge. Recent evidence implicates PRAS40 (AKT1S1) in regulating cellular survival and immune responses, but its role in immunotherapy resistance is not fully understood. METHODS: Transcriptomic data from TCGA and GTEx cohorts were analyzed to assess PRAS40 expression. Prognostic value was evaluated using Cox regression. Immune microenvironment features were characterized with CIBERSORT and TIMER. Predictive efficacy for ICB response was examined using TIDE and IPS. Plasma PRAS40 levels in 66 NSCLC patients receiving ICB were quantified by proximity extension assay (PEA), and multiplex immunohistochemistry assessed associations among PRAS40, PD-L1, and CD8+ T cells in tumor tissues. RESULTS: High PRAS40 expression was associated with poor prognosis, reduced CD8+ T cell infiltration, and downregulation of immune checkpoint genes. Elevated circulating PRAS40 predicted primary ICB resistance and shorter progression-free survival, independent of PD-L1 or CD8+ T cell status. CONCLUSION: PRAS40 is strongly associated with primary ICB resistance in NSCLC and may serve as a novel predictive biomarker. These findings support its potential to guide personalized immunotherapy in lung cancer.

Humans↗
PubMed2026

The evolution of Ca2+-ATPases across plants with profiles in Rhododendron and the function of key members in alleviating high calcium stress.

Ca2+-ATPase (CAP) is a key Ca2+ efflux protein in plants. Our previous research suggests that CAPs may play a crucial role in the adaptation of rhododendrons to high calcium environments. However, the evolution, variation, characteristic expression, and subfunctionalization of this gene family in Rhododendron remain unknown. Through the analysis of pan-genomes and pan-transcriptomes, we elucidated the systematic evolution of CAPs in plants, as well as their characteristic expression patterns in Rhododendron. During the evolutionary process from lower to higher plants, CAPs can be divided into six clades and exhibit structural conservation. CAPs have emerged and differentiated in lower plants such as algae, and they have undergone significant amplification in Eudicots plants like rhododendrons. Three Rhododendron species (Rhododendron bailiense, R. delavayi, and R. irroratum) located in the karst province of Guizhou in Southwest China exhibit the highest copies of CAPs, suggesting a strong association between CAP copy number variation and habitat, particularly in high calcium environments. Through multiple transcriptome analyses, we revealed that CAPs are induced under various environmental/developmental conditions (e.g. karst environments, high altitude, early flower development, hormones, etc.). Co-expression network analysis highlighted key members of calcineurin B-like protein (CBL) and CBL-interacting protein kinases (CIPK) that are associated with the high expression of CAPs. Experimental validation demonstrated that CAPb1 and CAPd1 significantly alleviate high calcium stress, and the CAPb1-CIPK1-CBL1 and CAPd1-CIPK2-CBL1 modules can further enhance the alleviation. These findings provide new insights into the evolution, characteristic expression, and function of CAPs, as well as new perspectives on the high calcium adaptability of rhododendrons.

Journal Article↗
PubMed2006

Differential brain transcriptome of beta4 nAChR subunit-deficient mice: is it the effect of the null mutation or the background strain?

Studies using mice with beta4 nicotinic acetylcholine receptor (nAChR) subunit deficiency (beta4-/- mice) helped reveal the roles of this subunit in bradycardiac response to vagal stimulation, nicotine-induced seizure activity and anxiety. To identify genes that might be related to beta4-containing nAChRs activity, we compared the mRNA expression profiles of brains from beta4-/- and wild-type mice using Affymetrix U74Av2 microarray. Seventy-seven genes significantly differentiated between these two experimental groups. Of them, the two most downregulated were spastic paraplegia 21 (human) homolog (Spg21) and 6-pyruvoyl-tetrahydropterin synthase (Pts) genes. Since the targeted mutagenesis of the beta4 nAChR subunit was done by using two mouse strains, 129SvEv and C57BL/6J, it is possible that the genes closely linked to the mutated beta4 gene represent the 129SvEv allele and not the control C57BL/6J-driven allele. We examined this possibility by using public database and quantitative RT-PCR. The expression levels of Spg21 and Pts genes that, like the beta4 gene, are localized on mouse chromosome 9, as well as the expression levels of other genes located on this chromosome, were dependent on the mouse background strain. The 67 differentially expressed genes that are not located on chromosome 9 were further analyzed for overrepresented functional annotations and transcription regulatory elements compared with the entire microarray. Genes encoding for proteins involved in tyrosine phosphatase activity, calcium ion binding, cell growth and/or maintenance, and chromosome organization were overrepresented. Our data enhance the understanding of the molecular interactions involved in the beta4 nAChR subunit function. They also emphasize the need for careful interpretation of expression microarray studies done on genetically manipulated animals.

Animals↗
PubMed2005

Gene expression profile associated with chronic atrial fibrillation and underlying valvular heart disease in man.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. The pathophysiology of AF involves electrical, structural and contractile remodeling, which is associated with changes in cardiac gene expression. Previous studies of gene-expression changes in clinical AF have mostly been limited to a small number of candidate genes and have not all been well controlled for underlying heart disease. The present study assessed AF-related gene-expression changes in valve-disease patients with microarrays representing the cardiac transcriptome. Right atrial appendages from 11 patients with chronic AF and underlying valvular heart disease (AF-VHD) and seven patients in sinus rhythm with VHD (SR-VHD) were individually compared to an age-matched sinus-rhythm control group (SR-CTRL, 11 patients) using cardiac-specific microarray analysis. One-class statistical analysis was used to identify genes differentially expressed between SR-VHD and SR-CTRL patients. Two-class statistical analysis was used to identify genes differentially expressed between AF-VHD and SR-VHD patients. Out of 3863 analyzed genes, 832 genes were differentially expressed between SR-VHD and SR-CTRL patients, and 169 genes were differentially expressed between AF-VHD and SR-VHD patients. Striking AF-related changes included altered expression of nine genes pointing towards the development of fibrosis (e.g. upregulation of transforming growth factor beta1), and changes in eight genes potentially related to an increased risk of thromboembolic events (e.g. upregulation of alpha2 macroglobulin). Microarray results were confirmed by quantitative PCR. Our results suggest that AF produces a characteristic profile of gene-expression changes that may be related to the pathophysiology of the arrhythmia.

Aged↗
PubMed2002

A computational/functional genomics approach for the enrichment of the retinal transcriptome and the identification of positional candidate retinopathy genes.

Grouping genes by virtue of their sequence similarity, functional association, or spatiotemporal distribution is an important first step in investigating function. Given the recent identification of >30,000 human genes either by analyses of genomic sequence or by derivation/assembly of ESTs, automated means of discerning gene function and association with disease are critical for the efficient processing of this large volume of data. We have designed a series of computational tools to manipulate the EST sequence database (dbEST) to predict EST clusters likely representing genes expressed exclusively or preferentially in a specific tissue. We implemented this tool by extracting 40,000 human retinal ESTs and performing in silico subtraction against 1.4 million human ESTs. This process yielded 925 ESTs likely to be specifically or preferentially expressed in the retina. We mapped all retinal-specific/predominant sequences in the human genome and produced a web-based searchable map of the retina transcriptome, onto which we overlaid the positions of all mapped but uncloned retinopathy genes. This resource has provided positional candidates for 42 of 51 uncloned retinopathies and may expedite substantially the identification of disease-associated genes. More importantly, the ability to systematically group ESTs according to their predicted expression profile is likely to be an important resource for studying gene function in a wide range of tissues and physiological systems and to identify positional candidate genes for human disorders whose phenotypic manifestations are restricted to specific tissues/organs/cell types.

Databases, Nucleic Acid↗
PubMed2026

Single-cell RNA sequencing reveals disease associated changes in brain endothelial cells in the 5XFAD mouse.

Vascular dysfunction is a key contributor to Alzheimer&#x2019;s disease (AD) pathology, where changes to the endothelium and its crucial role in maintaining blood-brain barrier (BBB) integrity have been of particular emphasis. The transgenic 5XFAD (5X Familial Alzheimer&#x2019;s Disease) mouse model, which exhibits AD-related amyloidosis through FAD associated mutations in amyloid precursor protein (APP) and presenilin-1 (PS1), has become a widely adopted preclinical model in AD-related research studies. The need for cross-study standardization, accessibility, and data reproducibility has led to the widespread implementation of the C57BL/6J genetic background for maintaining this model. However, its reliability for studying vascular dysfunction and BBB alterations has been questioned due to conflicting reports in the literature. This variation is often attributed to the previously documented protective nature of the C57BL/6J background and loss of genetic background diversity. Since prior studies have mostly relied on imaging or functional assays, we herein utilized single-cell RNA sequencing (scRNAseq) to investigate AD-related molecular changes to endothelial cell populations in the 5XFAD mouse model. To initially build this resource, we focused on 12-month-old male mice, which revealed differentially expressed genes between 5XFAD and wildtype animals that mapped to signaling pathways involved in DNA damage, immune reactivity, and inflammation, among others. Many of these transcriptomic changes were zonated along the arteriovenous axis and occurred in AD genome-wide association study (GWAS) risk-associated genes. Overall, we anticipate this resource will help clarify the use of the 5XFAD model for studying AD-associated vascular changes and provide the foundation for expanded molecular profiling of brain endothelial cells under AD-associated conditions.

Animals↗
PubMed2005

Genome-wide expression profiling of the host response to root-knot nematode infection in Arabidopsis.

During a compatible interaction, root-knot nematodes (Meloidogyne spp.) induce the redifferentiation of root cells into multinucleate nematode feeding cells (giant cells). Hyperplasia and hypertrophy of the surrounding cells leads to the formation of a root gall. We investigated the plant response to root-knot nematodes by carrying out a global analysis of gene expression during gall formation in Arabidopsis, using giant cell-enriched root tissues. Among 22 089 genes monitored with the complete Arabidopsis transcriptome microarray gene-specific tag, we identified 3373 genes that display significant differential expression between uninfected root tissues and galls at different developmental stages. Quantitative PCR analysis and the use of promoter GUS fusions confirmed the changes in mRNA levels observed in our microarray analysis. We showed that a comparable number of genes were found to be up- and downregulated, indicating that gene downregulation might be essential to allow proper gall formation. Moreover, many genes belonging to the same family are differently regulated in feeding cells. This genome-wide overview of gene expression during plant-nematode interaction provides new insights into nematode feeding-cell formation, and highlights that the suppression of plant defence is associated with nematode feeding-site development.

Animals↗