Transcriptomics reveal stretched human pluripotent stem cell-derived cardiomyocytes as an advantageous hypertrophy model

Left ventricular hypertrophy, characterized by hypertrophy of individual cardiomyocytes, is an adaptive response to an increased cardiac workload that eventually leads to heart failure. Previous studies using neonatal rat ventricular myocytes (NRVMs) and animal models have revealed several hypertrophy- and mechanical load-associated genes and signaling pathways. However, these models are not directly applicable to humans. Here, we studied the effect of cyclic mechanical stretch on gene expression of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using RNA sequencing. HiPSC-CMs showed distinct hypertrophic changes in gene expression at the level of individual genes and in biological processes. We also identified several differentially expressed genes that have not been previously associated with cardiomyocyte hypertrophy and thus serve as attractive targets for future studies. When compared to previously published data attained from stretched NRVMs and human embryonic stem cell-derived cardiomyocytes, hiPSC-CMs displayed a smaller number of changes in gene expression, but the differentially expressed genes revealed more pronounced enrichment of hypertrophy-related biological processes and pathways. Overall, these results establish hiPSC-CMs as a valuable in vitro model for studying human cardiomyocyte hypertrophy.

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Integrative Analysis of the Genes Induced by the Intestine Microbiota of Infant Born to Term and Breastfed

Bioinformatics and Biology Insights ◽

10.1177/1177932220906168 ◽

2020 ◽

Vol 14 ◽

pp. 117793222090616

Author(s):

Badreddine Nouadi ◽

Yousra Sbaoui ◽

Mariame El Messal ◽

Faiza Bennis ◽

Fatima Chegdani

Keyword(s):

Gene Expression ◽

Breast Milk ◽

Differentially Expressed Genes ◽

Bacterial Colonization ◽

Biological Data ◽

Integrative Analysis ◽

Differentially Expressed ◽

Epithelial Tissue ◽

Biological Processes

Nowadays, the integration of biological data is a major challenge for bioinformatics. Many studies have examined gene expression in the epithelial tissue in the intestines of infants born to term and breastfed, generating a large amount of data. The integration of these data is important to understand the biological processes involved during bacterial colonization of the newborns intestine, particularly through breast milk. This work aims to exploit the bioinformatics approaches, to provide a new representation and interpretation of the interactions between differentially expressed genes in the host intestine induced by the microbiota.

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Transcriptomic analysis of PPARα-dependent alterations during cardiac hypertrophy

Physiological Genomics ◽

10.1152/physiolgenomics.90296.2008 ◽

2008 ◽

Vol 36 (1) ◽

pp. 15-23 ◽

Cited By ~ 26

Author(s):

Pascal J. H. Smeets ◽

Heleen M. de Vogel-van den Bosch ◽

Peter H. M. Willemsen ◽

Alphons P. Stassen ◽

Torik Ayoubi ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Lipid Metabolism ◽

Cardiac Hypertrophy ◽

Signaling Pathways ◽

Differentially Expressed Genes ◽

Left Ventricular ◽

Transcriptomic Analysis ◽

Differentially Expressed ◽

Wild Type

Peroxisome proliferator-activated receptor (PPAR)α regulates lipid metabolism at the transcriptional level and modulates the expression of genes involved in inflammation, cell proliferation, and differentiation. Although PPARα has been shown to mitigate cardiac hypertrophy, knowledge about underlying mechanisms and the nature of signaling pathways involved is fragmentary and incomplete. The aim of this study was to identify the processes and signaling pathways regulated by PPARα in hearts challenged by a chronic pressure overload by means of whole genome transcriptomic analysis. PPARα−/− and wild-type mice were subjected to transverse aortic constriction (TAC) for 28 days, and left ventricular gene expression profile was determined with Affymetrix GeneChip Mouse Genome 430 2.0 arrays containing >45,000 probe sets. In unchallenged hearts, the mere lack of PPARα resulted in 821 differentially expressed genes, many of which are related to lipid metabolism and immune response. TAC resulted in a more pronounced cardiac hypertrophy and more extensive changes in gene expression (1,910 and 312 differentially expressed genes, respectively) in PPARα−/− mice than in wild-type mice. Many of the hypertrophy-related genes were related to development, signal transduction, actin filament organization, and collagen synthesis. Compared with wild-type hypertrophied hearts, PPARα−/− hypertrophied hearts revealed enrichment of gene clusters related to extracellular matrix remodeling, immune response, oxidative stress, and inflammatory signaling pathways. The present study therefore demonstrates that, in addition to lipid metabolism, PPARα is an important modulator of immune and inflammatory response in cardiac muscle.

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Identification of aberrantly methylated differentially expressed genes in melanoma

10.21203/rs.2.24149/v1 ◽

2020 ◽

Author(s):

Wei Han ◽

Guo-liang Shen

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Differentially Expressed Genes ◽

Enrichment Analysis ◽

Differentially Expressed ◽

Regulation Of Transcription ◽

Biological Processes ◽

Hub Genes ◽

Positive Regulation ◽

Upregulated Genes

Abstract Background: Skin Cutaneous Melanoma (SKCM) is known as an aggressive malignant cancer, which could be directly derived from melanocytic nevi. However, the molecular mechanisms underlying malignant transformation of melanocytes and melanoma tumor progression still remain unclear. Increasing researches showed significant roles of epigenetic modifications, especially DNA methylation, in melanoma. This study focused on identification and analysis of methylation-regulated differentially expressed genes (MeDEGs) between melanocytic nevus and malignant melanoma in genome-wide profiles. Methods: The gene expression profiling datasets (GSE3189 and GSE114445) and gene methylation profiling datasets (GSE86355 and GSE120878) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were identified via GEO2R. MeDEGs were obtained by integrating the DEGs and DMGs. Then, functional enrichment analysis of MeDEGs were performed. STRING and Cytoscape were used to describe protein-protein interaction(PPI) network. Furthermore, survival analysis was implemented to select the prognostic hub genes. Finally, we conducted gene set enrichment analysis (GSEA) of hub genes. Results: We identified 237 hypomethylated, upregulated genes and 182 hypermethylated, downregulated genes. Hypomethylation-upregulated genes were enriched in biological processes of the oxidation-reduction process, cell proliferation, cell division, phosphorylation, extracellular matrix disassembly and protein sumoylation. Pathway enrichment showed selenocompound metabolism, small cell lung cancer and lysosome. Hypermethylation-downregulated genes were enriched in biological processes of positive regulation of transcription from RNA polymerase II promoter, cell adhesion, cell proliferation, positive regulation of transcription, DNA-templated and angiogenesis. The most significantly enriched pathways involved the transcriptional misregulation in cancer, circadian rhythm, tight junction, protein digestion and absorption and Hippo signaling pathway. After PPI establishment and survival analysis, seven prognostic hub genes were CKS2, DTL, KIF2C, KPNA2, MYBL2, TPX2 and FBL. Moreover, the most involved hallmarks obtained by GSEA were E2F targets, G2M checkpoint and mitotic spindle. Conclusions: Our study identified potential aberrantly methylated-differentially expressed genes participating in the process of malignant transformation from nevus to melanoma tissues based on comprehensive genomic profiles. Transcription profiles of CKS2, DTL, KIF2C, KPNA2, MYBL2, TPX2 and FBL provided clues of aberrantly methylation-based biomarkers, which might improve the development of precise medicine.

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Abstract 342: Serum Albumin Hydrogels Alter Excitation-Contraction Coupling in Neonatal Rat Myocytes and Human Induced Pluripotent Stem Cell Derived Cardiomyocytes

Circulation Research ◽

10.1161/res.121.suppl_1.342 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Eleanor J Humphrey ◽

Manuel M Mazo ◽

Nadav Amdursky ◽

Nicholas S Peters ◽

Molly M Stevens ◽

...

Keyword(s):

Gene Expression ◽

Stem Cell ◽

Serum Albumin ◽

Pluripotent Stem Cell ◽

Induced Pluripotent Stem Cell ◽

Neonatal Rat ◽

Calcium Handling ◽

Time To Peak ◽

Induced Pluripotent ◽

Reduced Time

Tissue engineering provides a promising method of introducing functional cardiomyocytes (CMs) to damaged myocardium after myocardial infarction; however, finding a biocompatible construct with the chemical and mechanical properties capable of supporting CM function is challenging. Serum albumin hydrogels are novel autogenic scaffolds with elastic properties that can be tailored to mimic the stiffness of native adult myocardium. We assessed the hypothesis that culturing immature CMs on these serum albumin hydrogels would affect CM gene expression and calcium handling. Neonatal cardiomyocyte (NRVM) viability was maintained for at least 14 days on the hydrogels, with clear sarcomeric striations. Cardiac gene expression was quantified using RT-qPCR and demonstrated an up regulation in many genes of cells cultured on hydrogels compared to glass (e.g. relative expression (log 2-ΔΔCt) of ryanodine receptor 2: glass= -2.3±0.5, hydrogel= -0.3±0.1,p<0.01; connexin 43:glass= -1.7±0.5, hydrogel= 0.3±0.1,p<0.01,n=4-6). Compared to glass, NRVMs on hydrogels have an increased time to peak of the calcium transients measured using Fluo-4AM and field stimulated at 1 Hz (tp glass=38±3 ms, tp hydrogel= 54±2 ms, p<0.01,n=4-6). Compared to glass the hydrogels also have a reduced time 50% decay (t50 glass=108±13 ms, t50 hydrogel=78±6 ms, p<0.05,n=4-6) and 80% decay (t80 glass=217±19 ms, t80 hydrogel= 152±10 ms,p<0.05,n=4-6). Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) were cultured on the hydrogels for up to 28 days. Calcium handling was faster in the iPSC-CMs cultured on the hydrogels in comparison to glass with a reduced time to peak (tp glass=281±43 ms, tp hydrogel= 186±8 ms, p<0.05, n=4) and time to 50% decay (t50 glass=269±15 ms, t50 hydrogel=204±10 ms,p<0.01,n=4) and 90% decay (t90 glass=535±33 ms, t90 hydrogel=397±19 ms, p<0.01,n=4). The serum albumin hydrogels are compatible with NRVM and iPSC-CM culture for at least 28 days. We demonstrate that the serum albumin hydrogels have significant effects on CM calcium cycling and have the potential for use in myocardial repair. Further study is required to determine the mechanisms involved in calcium handling alterations and then assess this engineered patch in vivo for cardiac repair.

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E.PAGE: A curated database and enrichment tool to predict modules associated with gene-environment interactions

10.1101/2022.01.03.474848 ◽

2022 ◽

Author(s):

Sachin Muralidharan ◽

Farah Zahir ◽

Ahmed M. Mehdi

Keyword(s):

Gene Expression ◽

Statistical Analysis ◽

Environmental Factors ◽

Differentially Expressed Genes ◽

R Package ◽

Differentially Expressed ◽

Toxic Chemicals ◽

Biological Processes ◽

Analysis Package ◽

Gene Modules

Aims/hypothesis: The purpose of this study is to manually and semi-automatically curate a database and develop an R package that will act as a comprehensive resource to understand how biological processes are dysregulated due to interactions with environmental factors. Methods: We followed a two-step process to achieve the objectives of this study. First, we conducted a systematic review of the existing gene expression datasets to identify the integrated genomic and environmental factors used in available studies. This enabled us to curate a comprehensive genomic-environmental database for four key environmental factors (smoking, diet, infections and toxic chemicals) associated with various autoimmune and chronic conditions. Second, we developed a statistical analysis package that allows users to understand the relationships between differentially expressed genes and environmental factors under different disease conditions. Results: The initial database search run on the Gene Expression Omnibus (GEO) and the Molecular Signature Database (MSigDB) retrieved a total of 90,018 articles. After title and abstract screening against pre-set criteria, a total of 186 studies were selected. From those, 243 individual sets of genes, or gene modules, were obtained. We then curated a database containing four environmental factors, namely cigarette smoking, diet, infections and toxic chemicals, along with a total of 25789 genes that had an association with one or more of these factors. In 6 case studies, the database and statistical analysis package were then tested with lists of differentially expressed genes obtained from the published literature related to type 1 diabetes, rheumatoid arthritis, small cell lung cancer, cobalt exposure, COVID-19 and smoking. On testing, we uncovered statistically enriched biological processes, which could help us understand the pathways associated with environmental factors and gene modules. Conclusions: A novel curated database and software tool is provided as an R Package. Users can enter a list of genes to discover associated environmental factors under various disease conditions.

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Investigation of Aberrantly Methylated Differentially Expressed Genes in Pancreatic Cancer by Integrated Bioinformatics Analysis

10.21203/rs.3.rs-132250/v1 ◽

2021 ◽

Author(s):

Cailin xue ◽

Peng gao ◽

Xudong zhang ◽

Xiaohan cui ◽

Lei jin ◽

...

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Signaling Pathways ◽

Differentially Expressed Genes ◽

Dna Sequences ◽

Differentially Expressed ◽

Receptor Interaction ◽

Biological Processes ◽

Ppi Network ◽

Hub Genes

Abstract Background: Abnormal methylation of DNA sequences plays an important role in the development and progression of pancreatic cancer (PC). The purpose of this study was to identify abnormal methylation genes and related signaling pathways in PC by comprehensive bioinformatic analysis of three datasets in the Gene Expression Omnibus (GEO). Methods: Datasets of gene expression microarrays (GSE91035, GSE15471) and gene methylation microarrays (GSE37480) were downloaded from the GEO database. Aberrantly methylated-differentially expressed genes (DEGs) were analysis by GEO2R software. GO and KEGG enrichment analyses of selected genes were performed using DAVID database. A protein–protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape. Core module analysis was performed by Mcode in Cytoscape. Hub genes were obtained by CytoHubba app. in Cytoscape software. Results: A total of 267 hypomethylation-high expression genes, which were enriched in biological processes of cell adhesion, biological adhesion and regulation of signaling were obtained. KEGG pathway enrichment showed ECM-receptor interaction, Focal adhesion and PI3K-Akt signaling pathway. The top 5 hub genes of PPI network were EZH2, CCNA2, CDC20, KIF11, UBE2C. As for hypermethylation-low expression genes, 202 genes were identified, which were enriched in biological processes of cellular amino acid biosynthesis process and positive regulation of PI3K activity, etc. The pathways enriched were the pancreatic secretion and biosynthesis of amino acids pathways, etc. The five significant hub genes were DLG3, GPT2, PLCB1, CXCL12 and GNG7. In addition, five genes, including CCNA2, KIF11, UBE2C, PLCB1 and GNG7, significantly associated with patient's prognosis were also identified. Conclusion: Novel genes with abnormal expression were identified, which will help us further understand the molecular mechanism and related signaling pathways of PC, and these aberrant genes could possibly serve as biomarkers for precise diagnosis and treatment of PC.

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Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response

Journal of Personalized Medicine ◽

10.3390/jpm11111047 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1047

Author(s):

Justin Bo-Kai Hsu ◽

Tzong-Yi Lee ◽

Sho-Jen Cheng ◽

Gilbert Aaron Lee ◽

Yung-Chieh Chen ◽

...

Keyword(s):

Gene Expression ◽

Stem Cell ◽

Cancer Stem Cell ◽

Single Cell ◽

Differentially Expressed Genes ◽

Tumor Recurrence ◽

Differentially Expressed ◽

Ppi Network ◽

Gene Signatures ◽

Key Genes

The molecular heterogeneity of gene expression profiles of glioblastoma multiforme (GBM) are the most important prognostic factors for tumor recurrence and drug resistance. Thus, the aim of this study was to identify potential target genes related to temozolomide (TMZ) resistance and GBM recurrence. The genomic data of patients with GBM from The Cancer Genome Atlas (TCGA; 154 primary and 13 recurrent tumors) and a local cohort (29 primary and 4 recurrent tumors), samples from different tumor regions from a local cohort (29 tumor and 25 peritumoral regions), and Gene Expression Omnibus data (GSE84465, single-cell RNA sequencing; 3589 cells) were included in this study. Critical gene signatures were identified based an analysis of differentially expressed genes (DEGs). DEGs were further used to evaluate gene enrichment levels among primary and recurrent GBMs and different tumor regions through gene set enrichment analysis. Protein–protein interactions (PPIs) were incorporated into gene regulatory networks to identify the affected metabolic pathways. The enrichment levels of 135 genes were identified in the peritumoral regions as being risk signatures for tumor recurrence. Fourteen genes (DVL1, PRKACB, ARRB1, APC, MAPK9, CAMK2A, PRKCB, CACNA1A, ERBB4, RASGRF1, NF1, RPS6KA2, MAPK8IP2, and PPM1A) derived from the PPI network of 135 genes were upregulated and involved in the regulation of cancer stem cell (CSC) development and relevant signaling pathways (Notch, Hedgehog, Wnt, and MAPK). The single-cell data analysis results indicated that 14 key genes were mainly expressed in oligodendrocyte progenitor cells, which could produce a CSC niche in the peritumoral region. The enrichment levels of 336 genes were identified as biomarkers for evaluating TMZ resistance in the solid tumor region. Eleven genes (ARID5A, CDC42EP3, CDKN1A, FLT3, JUNB, MAP2K3, MYBPC2, RGS14, RNASEK, TBC1D30, and TXNDC11) derived from the PPI network of 336 genes were upregulated and may be associated with a high risk of TMZ resistance; these genes were identified in both the TCGA and local cohorts. Furthermore, the expression patterns of ARID5A, CDKN1A, and MAP2K3 were identical to the gene signatures of TMZ-resistant cell lines. The identified enrichment levels of the two gene sets expressed in tumor and peritumoral regions are potentially helpful for evaluating TMZ resistance in GBM. Moreover, these key genes could be used as biomarkers, potentially providing new molecular strategies for GBM treatment.

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Induced pluripotent stem cell–based mapping of β-globin expression throughout human erythropoietic development

Blood Advances ◽

10.1182/bloodadvances.2018020560 ◽

2018 ◽

Vol 2 (15) ◽

pp. 1998-2011 ◽

Cited By ~ 8

Author(s):

Kim Vanuytsel ◽

Taylor Matte ◽

Amy Leung ◽

Zaw Htut Naing ◽

Tasha Morrison ◽

...

Keyword(s):

Gene Expression ◽

Stem Cell ◽

Expression Profile ◽

Pluripotent Stem Cell ◽

Induced Pluripotent Stem Cell ◽

Yolk Sac ◽

Biological Processes ◽

Erythroid Cells ◽

Key Points ◽

Induced Pluripotent

Key Points iPSC-derived definitive erythroid cells display a globin expression profile corresponding to yolk sac erythromyeloid progenitors. iPSC-derived erythroblasts resemble their postnatal counterparts in terms of gene expression and essential biological processes.

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Effects of threshold choice on the results of gene expression profiling, using microarray analysis, in a model feeding experiment with rats

Archives Animal Breeding ◽

10.5194/aab-52-65-2009 ◽

2009 ◽

Vol 52 (1) ◽

pp. 65-78

Author(s):

A. Hartmann ◽

G. Nuernberg ◽

D. Repsilber ◽

P. Janczyk ◽

C. Walz ◽

...

Keyword(s):

Gene Expression ◽

Differentially Expressed Genes ◽

Microarray Data ◽

Expression Profiling ◽

High Reliability ◽

Food Additives ◽

Fold Change ◽

Differentially Expressed ◽

Biological Processes ◽

Feeding Experiment

Abstract. Global gene expression studies using microarray technology are widely employed to identify biological processes which are influenced by a treatment e.g. a specific diet. Affected processes are characterized by a significant enrichment of differentially expressed genes (functional annotation analysis). However, different choices of statistical thresholds to select candidates for differential expression will alter the resulting candidates list. This study was conducted to investigate the effect of applying a False Discovery Rate (FDR) correction and different fold change thresholds in statistical analysis of microarray data on diet-affected biological processes based on a significantly increased proportion of differentially expressed genes. In a model feeding experiment with rats fed genetically modified food additives, animals received a supplement of either lyophilized inactivated recombinant VP60 baculovirus (rBV-VP60) or lyophilized inactivated wild type baculovirus (wtBV). Comparative expression profiling was done in spleen, liver and small intestine mucosa. We demonstrated the extent to which threshold choice can affect the biological processes identified as significantly regulated and thus the conclusion drawn from the microarray data. In our study, the combined application of a moderate fold change threshold (FC≥1.5) and a stringent FDR threshold (q≤0.05) exhibited high reliability of biological processes identified as differentially regulated. The application of a stringent FDR threshold of q≤0.05 seems to be an essential prerequisite to reduce considerably the number of false positives. Microarray results of selected differentially expressed molecules were validated successfully by using real-time RT-PCR.

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Association of Wolbachia with gene expression in Drosophila testes

10.21203/rs.3.rs-188597/v1 ◽

2021 ◽

Author(s):

Weihao Dou ◽

Yunheng Miao ◽

Jinhua Xiao ◽

Dawei Huang

Keyword(s):

Gene Expression ◽

Differentially Expressed Genes ◽

Differentially Expressed ◽

Symbiotic Bacteria ◽

Biological Processes ◽

Lysosomal Degradation ◽

Additional Information ◽

The Relationship ◽

Sperm Dysfunction ◽

Compare Gene Expression

Abstract Wolbachia is a genus of intracellular symbiotic bacteria that are widely distributed in arthropods and nematodes. These maternally inherited bacteria regulate host reproductive systems in various ways to facilitate their vertical transmission. Since the identification of Wolbachia in many insects, the relationship between Wolbachia and the host has attracted great interest. Numerous studies have indicated that Wolbachia modifies a variety of biological processes in the host. Previous studies in Drosophila melanogaster (D. mel) have demonstrated that Wolbachia can affect spermatid differentiation, chromosome deposition, and sperm activity in the early stages of spermatogenesis, leading to sperm dysfunction. Here, we explored the putative effect of Wolbachia in sperm maturation using transcriptomic approaches to compare gene expression in Wolbachia-infected and Wolbachia-free D. mel adult testes. Our findings show that Wolbachia affects many biological processes in D. mel adult testes, and most of the differentially expressed genes involved in carbohydrate metabolism, lysosomal degradation, proteolysis, lipid metabolism, and immune response were upregulated in the presence of Wolbachia. In contrast, some genes that are putatively associated with cutin and wax biosynthesis and peroxisome pathways were downregulated. We did not find any differentially expressed genes that are predicted to be related to spermatogenesis in the datasets. This work provides additional information for understanding the Wolbachia-host intracellular relationships.

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