Molecular Profiling of Glatiramer Acetate Early Treatment Effects in Multiple Sclerosis

Background: Glatiramer acetate (GA, Copaxone®) has beneficial effects on the clinical course of relapsing-remitting multiple sclerosis (RRMS). However, the exact molecular mechanisms of GA effects are only partially understood.Objective: To characterized GA molecular effects in RRMS patients within 3 months of treatment by microarray profiling of peripheral blood mononuclear cells (PBMC).Methods: Gene-expression profiles were determined in RRMS patients before and at 3 months after initiation of GA treatment using Affimetrix (U133A-2) microarrays containing 14,500 well-characterized human genes. Most informative genes (MIGs) of GA-induced biological convergent pathways operating in RRMS were constructed using gene functional annotation, enrichment analysis and pathway reconstruction bioinformatic softwares. Verification at the mRNA and protein level was performed by qRT-PCR and FACS.Results: GA induced a specific gene expression molecular signature that included altered expression of 480 genes within 3 months of treatment; 262 genes were up-regulated, and 218 genes were down-regulated. The main convergent mechanisms of GA effects were related to antigen-activated apoptosis, inflammation, adhesion, and MHC class-I antigen presentation.Conclusions: Our findings demonstrate that GA treatment induces alternations of immunomodulatory gene expression patterns that are important for suppression of disease activity already at three months of treatment and can be used as molecular markers of GA activity.

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Analysis of the transcriptome of bovine endometrial cells isolated by laser micro-dissection (1): specific signatures of stromal, glandular and luminal epithelial cells

BMC Genomics ◽

10.1186/s12864-021-07712-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Wiruntita Chankeaw ◽

Sandra Lignier ◽

Christophe Richard ◽

Theodoros Ntallaris ◽

Mariam Raliou ◽

...

Keyword(s):

Gene Expression ◽

Protein Localization ◽

Expression Profiles ◽

Cell Types ◽

Molecular Signature ◽

Receptor Protein ◽

Specific Gene ◽

Specific Cell ◽

Biological Processes ◽

Endometrial Cells

Abstract Background A number of studies have examined mRNA expression profiles of bovine endometrium at estrus and around the peri-implantation period of pregnancy. However, to date, these studies have been performed on the whole endometrium which is a complex tissue. Consequently, the knowledge of cell-specific gene expression, when analysis performed with whole endometrium, is still weak and obviously limits the relevance of the results of gene expression studies. Thus, the aim of this study was to characterize specific transcriptome of the three main cell-types of the bovine endometrium at day-15 of the estrus cycle. Results In the RNA-Seq analysis, the number of expressed genes detected over 10 transcripts per million was 6622, 7814 and 8242 for LE, GE and ST respectively. ST expressed exclusively 1236 genes while only 551 transcripts were specific to the GE and 330 specific to LE. For ST, over-represented biological processes included many regulation processes and response to stimulus, cell communication and cell adhesion, extracellular matrix organization as well as developmental process. For GE, cilium organization, cilium movement, protein localization to cilium and microtubule-based process were the only four main biological processes enriched. For LE, over-represented biological processes were enzyme linked receptor protein signaling pathway, cell-substrate adhesion and circulatory system process. Conclusion The data show that each endometrial cell-type has a distinct molecular signature and provide a significantly improved overview on the biological process supported by specific cell-types. The most interesting result is that stromal cells express more genes than the two epithelial types and are associated with a greater number of pathways and ontology terms.

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Convergent evolution of venom gland transcriptomes across Metazoa

10.1101/2021.07.04.451048 ◽

2021 ◽

Author(s):

Giulia Zancolli ◽

Maarten Reijnders ◽

Robert Waterhouse ◽

Marc Robinson-Rechavi

Keyword(s):

Gene Expression ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Venom Gland ◽

Bioactive Molecules ◽

Specific Gene ◽

Animal Kingdom ◽

Venom Glands

Animals have repeatedly evolved specialized organs and anatomical structures to produce and deliver a cocktail of potent bioactive molecules to subdue prey or predators: venom. This makes it one of the most widespread convergent functions in the animal kingdom. Whether animals have adopted the same genetic toolkit to evolved venom systems is a fascinating question that still eludes us. Here, we performed the first comparative analysis of venom gland transcriptomes from 20 venomous species spanning the main Metazoan lineages, to test whether different animals have independently adopted similar molecular mechanisms to perform the same function. We found a strong convergence in gene expression profiles, with venom glands being more similar to each other than to any other tissue from the same species, and their differences closely mirroring the species phylogeny. Although venom glands secrete some of the fastest evolving molecules (toxins), their gene expression does not evolve faster than evolutionarily older tissues. We found 15 venom gland specific gene modules enriched in endoplasmic reticulum stress and unfolded protein response pathways, indicating that animals have independently adopted stress response mechanisms to cope with mass production of toxins. This, in turns, activates regulatory networks for epithelial development, cell turnover and maintenance which seem composed of both convergent and lineage-specific factors, possibly reflecting the different developmental origins of venom glands. This study represents the first step towards an understanding of the molecular mechanisms underlying the repeated evolution of one of the most successful adaptive traits in the animal kingdom.

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Dysregulation of MS risk genes and pathways at distinct stages of disease

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000337 ◽

2017 ◽

Vol 4 (3) ◽

pp. e337 ◽

Cited By ~ 16

Author(s):

Sundararajan Srinivasan ◽

Marco Di Dario ◽

Alessandra Russo ◽

Ramesh Menon ◽

Elena Brini ◽

...

Keyword(s):

Gene Expression ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Gene List ◽

Literature Mining ◽

Specific Gene ◽

Healthy Population ◽

Gene Expressions ◽

Altered Expression ◽

Risk Genes

Objective:To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions.Methods:We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining.Results:Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage–specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS.Conclusions:Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways.

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Short- and long-term impact of hyperoxia on the blood and retinal cells’ transcriptome in a mouse model of oxygen-induced retinopathy

Pediatric Research ◽

10.1038/s41390-019-0598-y ◽

2019 ◽

Vol 87 (3) ◽

pp. 485-493 ◽

Cited By ~ 1

Author(s):

Magdalena Zasada ◽

Anna Madetko-Talowska ◽

Cecilie Revhaug ◽

Anne Gro W. Rognlien ◽

Lars O. Baumbusch ◽

...

Keyword(s):

Gene Expression ◽

Mononuclear Cells ◽

Expression Patterns ◽

Control Group ◽

Global Pattern ◽

Retinal Cells ◽

Altered Expression ◽

Oxygen Induced Retinopathy ◽

Blood Mononuclear Cells ◽

Long Term Impact

Abstract Background We aimed to identify global blood and retinal gene expression patterns in murine oxygen-induced retinopathy (OIR), a common model of retinopathy of prematurity, which may allow better understanding of the pathogenesis of this severe ocular prematurity complication and identification of potential blood biomarkers. Methods A total of 120 C57BL/6J mice were randomly divided into an OIR group, in which 7-day-old pups were maintained in 75% oxygen for 5 days, or a control group. RNA was extracted from the whole-blood mononuclear cells and retinal cells on days 12, 17, and 28. Gene expression in the RNA samples was evaluated with mouse gene expression microarrays. Results There were 38, 1370 and 111 genes, the expression of which differed between the OIR and control retinas on days 12, 17, and 28, respectively. Gene expression in the blood mononuclear cells was significantly altered only on day 17. Deptor and Nol4 genes showed reduced expression both in the blood and retinal cells on day 17. Conclusion There are sustained marked changes in the global pattern of gene expression in the OIR mice retinas. An altered expression of Deptor and Nol4 genes in the blood mononuclear cells requires further investigation as they may indicate retinal neovascularization.

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Transcriptome Profiling of Adipose Tissue Reveals Depot-Specific Metabolic Alterations Among Patients with Colorectal Cancer

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00461 ◽

2019 ◽

Vol 104 (11) ◽

pp. 5225-5237 ◽

Cited By ~ 3

Author(s):

Mariam Haffa ◽

Andreana N Holowatyj ◽

Mario Kratz ◽

Reka Toth ◽

Axel Benner ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Adipose Tissue ◽

Large Scale ◽

Expression Profiles ◽

Expression Patterns ◽

Human Study ◽

Subcutaneous Fat ◽

Specific Gene ◽

Adipose Tissue Depots

Abstract Context Adipose tissue inflammation and dysregulated energy homeostasis are key mechanisms linking obesity and cancer. Distinct adipose tissue depots strongly differ in their metabolic profiles; however, comprehensive studies of depot-specific perturbations among patients with cancer are lacking. Objective We compared transcriptome profiles of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from patients with colorectal cancer and assessed the associations of different anthropometric measures with depot-specific gene expression. Design Whole transcriptomes of VAT and SAT were measured in 233 patients from the ColoCare Study, and visceral and subcutaneous fat area were quantified via CT. Results VAT compared with SAT showed elevated gene expression of cytokines, cell adhesion molecules, and key regulators of metabolic homeostasis. Increased fat area was associated with downregulated lipid and small molecule metabolism and upregulated inflammatory pathways in both compartments. Comparing these patterns between depots proved specific and more pronounced gene expression alterations in SAT and identified unique associations of integrins and lipid metabolism–related enzymes. VAT gene expression patterns that were associated with visceral fat area poorly overlapped with patterns associated with self-reported body mass index (BMI). However, subcutaneous fat area and BMI showed similar associations with SAT gene expression. Conclusions This large-scale human study demonstrates pronounced disparities between distinct adipose tissue depots and reveals that BMI poorly correlates with fat mass–associated changes in VAT. Taken together, these results provide crucial evidence for the necessity to differentiate between distinct adipose tissue depots for a correct characterization of gene expression profiles that may affect metabolic health of patients with colorectal cancer.

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Circulating melanoma cells isolated from clinical blood samples and characterized by full-length mRNA sequencing at single-cell level.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.10539 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 10539-10539 ◽

Cited By ~ 1

Author(s):

Yu-Chieh Wang ◽

Daniel Ramskold ◽

Shujun Luo ◽

Robin Li ◽

Qiaolin Deng ◽

...

Keyword(s):

Gene Expression ◽

Single Cell ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Expression Patterns ◽

Melanoma Cells ◽

Clinical Samples ◽

Single Cell Level ◽

Cell Level ◽

Blood Samples

10539 Background: Melanoma is the most aggressive type of skin cancer. Late-stage melanoma is highly metastatic and currently lacks effective treatment. This discouraging clinical observation highlights the need for a better understanding of the molecular mechanisms underlying melanoma initiation and progression and for developing new therapeutic approaches based on novel targets. Although genome-wide transcriptome analyses have been frequently used to study molecular alterations in clinical samples, it has been technically challenging to obtain the transcriptomic profiles at single-cell level. Methods: Using antibody-mediated magnetic activated cell separation (MACS), we isolated and individualized putative circulating melanoma cells (CMCs) from the blood samples of the melanoma patients at advance stages. The transcriptomic analysis based on a novel and robust mRNA-Seq protocol (Smart-Seq) was established and applied to the putative CMCs for single-cell profiling. Results: We have discovered distinct gene expression patterns, including new putative markers for CMCs. Meanwhile, the gene expression profiles derived of the CMC candidates isolated from the patient’s blood samples are closely-related to the expression profiles of other cells originated from human melanocytes, including normal melanocytes in primary culture and melanoma cell lines. Compared with existing methods, Smart-Seq has improved read coverage across transcripts, which provides advantage for better analyzing transcript isoforms and SNPs. Conclusions: Our results suggest that the techniques developed in this research for cell isolation and transcriptomic analyses can potentially be used for addressing many biological and clinical questions requiring genomewide transcriptome profiling in rare cells.

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Gene expression profiles during short-term heat stress; branchingvs.massive Scleractinian corals of the Red Sea

PeerJ ◽

10.7717/peerj.1814 ◽

2016 ◽

Vol 4 ◽

pp. e1814 ◽

Cited By ~ 14

Author(s):

Keren Maor-Landaw ◽

Oren Levy

Keyword(s):

Gene Expression ◽

Heat Stress ◽

Redox Regulation ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Expression Patterns ◽

Gene Expression Profiles ◽

Marker Genes ◽

Stylophora Pistillata ◽

Stress Genes

It is well-established that there is a hierarchy of susceptibilities amongst coral genera during heat-stress. However, molecular mechanisms governing these differences are still poorly understood. Here we explored if specific corals possessing different morphologies and different susceptibilities to heat stress may manifest varied gene expression patterns. We examined expression patterns of seven genes in the branching coralsStylophora pistillataandAcropora eurystomaand additionally in the massive robust coral,Poritessp. The tested genes are representatives of key cellular processes occurring during heat-stress in Cnidaria: oxidative stress, ER stress, energy metabolism, DNA repair and apoptosis. Varied response to the heat-stress, in terms of visual coral paling, algal maximum quantum yield and host gene expression was evident in the different growth forms. The two branching corals exhibited similar overall responses that differed from that of the massive coral.A. eurystomathat is considered as a susceptible species did not bleach in our experiment, but tissue sloughing was evident at 34 °C. Interestingly, in this species redox regulation genes were up-regulated at the very onset of the thermal challenge. InS. pistillata, bleaching was evident at 34 °C and most of the stress markers were already up-regulated at 32 °C, either remaining highly expressed or decreasing when temperatures reached 34 °C. The massivePoritesspecies displayed severe bleaching at 32 °C but stress marker genes were only significantly elevated at 34 °C. We postulate that by expelling the algal symbionts fromPoritestissues, oxidation damages are reduced and stress genes are activated only at a progressed stage. The differential gene expression responses exhibited here can be correlated with the literature well-documented hierarchy of susceptibilities amongst coral morphologies and genera in Eilat’s coral reef.

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Dysregulation of microRNA Modulatory Network in Abdominal Aortic Aneurysm

Journal of Clinical Medicine ◽

10.3390/jcm9061974 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1974 ◽

Cited By ~ 1

Author(s):

Daniel P. Zalewski ◽

Karol P. Ruszel ◽

Andrzej Stępniewski ◽

Dariusz Gałkowski ◽

Jacek Bogucki ◽

...

Keyword(s):

Gene Expression ◽

Mononuclear Cells ◽

Expression Profiles ◽

Differential Expression Analysis ◽

Artery Aneurysm ◽

Aortic Dilatation ◽

Operating Characteristics ◽

Peripheral Blood Mononuclear ◽

Altered Expression ◽

Abdominal Aortic

Abdominal artery aneurysm (AAA) refers to abdominal aortic dilatation of 3 cm or greater. AAA is frequently underdiagnosed due to often asymptomatic character of the disease, leading to elevated mortality due to aneurysm rupture. MiRNA constitute a pool of small RNAs controlling gene expression and is involved in many pathologic conditions in human. Targeted panel detecting altered expression of miRNA and genes involved in AAA would improve early diagnosis of this disease. In the presented study, we selected and analyzed miRNA and gene expression signatures in AAA patients. Next, generation sequencing was applied to obtain miRNA and gene-wide expression profiles from peripheral blood mononuclear cells in individuals with AAA and healthy controls. Differential expression analysis was performed using DESeq2 and uninformative variable elimination by partial least squares (UVE-PLS) methods. A total of 31 miRNAs and 51 genes were selected as the most promising biomarkers of AAA. Receiver operating characteristics (ROC) analysis showed good diagnostic ability of proposed biomarkers. Genes regulated by selected miRNAs were determined in silico and associated with functional terms closely related to cardiovascular and neurological diseases. Proposed biomarkers may be used for new diagnostic and therapeutic approaches in management of AAA. The findings will also contribute to the pool of knowledge about miRNA-dependent regulatory mechanisms involved in pathology of that disease.

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Molecular Phenotype of Malignant CD34+ Hematopoietic Stem and Progenitor Cells in Chronic Myelogenous Leukemia.

Blood ◽

10.1182/blood.v106.11.2863.2863 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2863-2863

Author(s):

Ralf Kronenwett ◽

Elena Diaz-Blanco ◽

Thorsten Graef ◽

Ulrich Steidl ◽

Slawomir Kliszewski ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Expression Profiles ◽

Expression Patterns ◽

Gene Expression Pattern ◽

Leukemic Cell ◽

Differentially Expressed ◽

Specific Gene ◽

Hematopoietic Stem ◽

Cd34 Cells

Abstract In this study, we examined gene expression profiles of immunomagnetically enriched CD34+ cells from bone marrow (BM) of 9 patients with untreated CML in chronic phase and from 8 healthy volunteers using Affymetrix GeneChips. Additionally, in 3 patients CD34+ from peripheral blood (PB) were compared with those from BM. Differential expression of 12 candidate genes was corroborated by quantitative real-time RT-PCR. Following hybridization of labelled cRNA to Affymetrix GeneChips covering 8793 genes we used the statistical scripting language “R” for data analysis. For normalization a method of variance stabilization transformations was used. To identify significantly differentially expressed genes we used the Significance Analysis of Microarrays (SAM) algorithm. The intraindividual comparison of CD34+ cells from BM and PB in CML showed no differentially expressed genes which is different to normal CD34+ cells which had distinct gene expression patterns comparing circulating and sedentary CD34+ cells (Steidl et al., Blood, 2002). Comparing malignant BM CD34+ cells from CML with normal BM CD34+ cells 792 genes were significantly differentially expressed (fold change: >1.3; q-value: <0.03). 735 genes had a higher and 57 genes a lower expression in CML. Gene expression patterns reflected BCR-ABL-induced functional alterations such as increased cell-cycle and proteasome activity as well as decreased apoptosis. Downregulation of several genes involved in DNA repair and detoxification in CML might be the basis for DNA instability and progression to blast crisis. An interesting finding was an upregulation of fetal hemoglobin (Hb) components such as Hb gamma A and G in leukemic progenitor cells whereas no difference in adult Hb expression was observed suggesting an induction of fetal Hb synthesis in CML. Looking at genes involved in stem cell maintenance we found an upregulation of GATA2 and a reduced expression of proteins from the Wnt signalling pathway suggesting an increased self-renewal of CML hematopoietic stem cells compared to the normal counterpart. Moreover, several genes playing a role in ubiquitin-dependent protein catabolism and in fatty acid biosynthesis such as fatty acid synthase (FAS) were stronger expressed in CML. The functional role of FAS for leukemic cell growth was assessed in cell culture experiments. Incubation of the leukemic cell line K562 with the FAS inhibitor cerulenin (10 μg/ml) for 3 days resulted in death of 99% of cells suggesting that survival of leukemic cells depends upon endogenous fatty acid synthesis. In an attempt to find a specific gene expression pattern associated with response to imatinib therapy we divided the patients included in this study into two groups: maximal reduction of BCR-ABL transcript level <3-log vs. >3-log (major molecular remission) during therapy. Comparing pretherapeutic gene expression profiles of both groups we could not identify a pattern predictive for major molecular response. In conclusion, malignant CD34+ cells in CML have a specific gene expression pattern which seems not to be predictive for response to imatinib therapy.

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Differential gene expression profiles of invasive and non-invasive non-functioning pituitary adenomas based on microarray analysis

Endocrine Related Cancer ◽

10.1677/erc-10-0018 ◽

2010 ◽

Vol 17 (2) ◽

pp. 361-371 ◽

Cited By ~ 49

Author(s):

Françoise Galland ◽

Ludovic Lacroix ◽

Patrick Saulnier ◽

Philippe Dessen ◽

Geri Meduri ◽

...

Keyword(s):

Gene Expression ◽

Pituitary Adenomas ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Molecular Signature ◽

Specific Gene ◽

Tumor Invasiveness ◽

Non Invasive ◽

Qrt Pcr ◽

Non Functioning Pituitary Adenomas

Non-functioning pituitary adenomas (NFPAs) may be locally invasive. Markers of invasiveness are needed to guide patient management and particularly the use of adjuvant radiotherapy. To examine whether invasive NFPAs display a specific gene expression profile relative to non-invasive tumors, we selected 40 NFPAs (38 of the gonadotroph type) and classified them as invasive (n=22) or non-invasive (n=18) on the basis of magnetic resonance imaging and surgical findings. We then performed pangenomic analysis with the 44k Agilent human whole genome expression oligonucleotide microarray in order to identify genes with differential expression between invasive and non-invasive NFPAs. Candidate genes were then tested in qRT-PCR. Prediction class analysis showed that the expression of 346 genes differed between invasive and non-invasive NFPAs (P<0.001), of which 233 genes were up-regulated and 113 genes were down-regulated in invasive tumors. On the basis of Ingenuity networks and the degree of up- or down-regulation in invasive versus non-invasive tumors, 35 genes were selected for expression quantification by qRT-PCR. Overexpression of only four genes was confirmed, namely IGFBP5 (P=0.02), MYO5A (P=0.04), FLT3 (P=0.01), and NFE2L1 (P=0.02). At the protein level, only myosin 5A (MYO5A) immunostaining was stronger in invasive than in non-invasive NFPAs. Molecular signature allows to differentiate ‘grossly’ invasive from non-invasive NFPAs. The product of one of these genes, MYO5A, may be a useful marker of tumor invasiveness.

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