Common signatures for gene expression in postnatal patients with patent arterial ducts and stented arteries

2009 ◽  
Vol 19 (4) ◽  
pp. 352-359 ◽  
Peter P. Mueller ◽  
Andreas Drynda ◽  
Diane Goltz ◽  
René Hoehn ◽  
Hansjörg Hauser ◽  

AbstractThe detailed molecular processes associated with postnatal remodelling of blood vessels are presently not understood. To characterize the response of the patients undergoing stenting of the patent arterial duct, we harvested samples of vascular tissue during surgical repair. Histological analysis of explanted ducts confirmed the patency of the ducts immediately after birth. As expected, a previously unstented duct that was examined 7 months after birth had become closed and ligamentous. Whole genome expression profiling of these samples showed that a large fraction, over 10%, of the gene sequences examined were expressed differentially between the samples taken from patients with open as opposed to the ligamentous duct. Interestingly, in 2 patients in whom closure was prevented by insertion of stents, one showed an expression profile that was similar to that of the patient initially having an unstented open duct, whereas the other was more closely related to the profile of the patient with a duct that had become ligamentous. Moreover, in 2 specimens obtained from patients with stented pulmonary arteries, a large fraction of the genes that were differentially expressed were identical to the pattern seen in the samples from the patients with open ducts. The gene regulation appeared to be independent of the nature of the respective malformations, and the site of implantation of the stents. These findings suggest that a set of differentially expressed genes are indicative for a transcriptional programme in neonatal remodelling of the arterial duct, which may also take place in patients in whom ductal closure is prevented by stents, or in those with stented pulmonary arteries. The differentially expressed genes included a significant number of extracellular matrix synthetic genes, and could therefore be predictive for vascular remodelling and neointimal formation.

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1059-1079 ◽  
Virginia D. Winn ◽  
Ronit Haimov-Kochman ◽  
Agnes C. Paquet ◽  
Y. Jean Yang ◽  
M. S. Madhusudhan ◽  

Human placentation entails the remarkable integration of fetal and maternal cells into a single functional unit. In the basal plate region (the maternal-fetal interface) of the placenta, fetal cytotrophoblasts from the placenta invade the uterus and remodel the resident vasculature and avoid maternal immune rejection. Knowing the molecular bases for these unique cell-cell interactions is important for understanding how this specialized region functions during normal pregnancy with implications for tumor biology and transplantation immunology. Therefore, we undertook a global analysis of the gene expression profiles at the maternal-fetal interface. Basal plate biopsy specimens were obtained from 36 placentas (14–40 wk) at the conclusion of normal pregnancies. RNA was isolated, processed, and hybridized to HG-U133A&B Affymetrix GeneChips. Surprisingly, there was little change in gene expression during the 14- to 24-wk interval. In contrast, 418 genes were differentially expressed at term (37–40 wk) as compared with midgestation (14–24 wk). Subsequent analyses using quantitative PCR and immunolocalization approaches validated a portion of these results. Many of the differentially expressed genes are known in other contexts to be involved in differentiation, motility, transcription, immunity, angiogenesis, extracellular matrix dissolution, or lipid metabolism. One sixth were nonannotated or encoded hypothetical proteins. Modeling based on structural homology revealed potential functions for 31 of these proteins. These data provide a reference set for understanding the molecular components of the dialogue taking place between maternal and fetal cells in the basal plate as well as for future comparisons of alterations in this region that occur in obstetric complications.

2020 ◽  
Shuaijun Chen ◽  
Jun Zhang ◽  
Wanli Ma ◽  
Hong Ye

Abstract BackgroundIdiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and fatal fibrotic lung disease all over the world, and specific pathogenesis is still not well understood. DNA methylation is an essential epigenetic mechanism, which likely contributes to the progress of IPF. The purpose of this study is to identify aberrantly methylated differentially expressed genes (DEGs) in IPF and to explore the underlying mechanisms of IPF by using integrated bioinformatics analysis.MethodGene expression profiles and gene methylation profile were downloaded and analyzed to identify the aberrantly methylated‐differentially expressed genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Search Tool for the Retrieval of Interacting Genes Database (STRING) and Gene set enrichment analysis (GSEA) were used to evaluate function of DEGs. RT-PCR was used to verify the mRNA levels of DEGs in mice with pulmonary fibrosis.ResultsBy analyzing the differentially expressed genes of the three IPF expression profiles, and taking the intersection, we got 143 co-upregulated genes and 104 co-downregulated genes; GO and KEGG pathway analysis of the DEGs suggested these genes involved in the extracellular matrix organization, multicellular organismal homeostasis. Combining the sequencing data of two IPF methylation chips, we have identified genes that may be regulated by methylation in IPF. Finally, we obtained the mRNA expression of DEGs using a mouse model of pulmonary fibrosis.ConclusionThrough integrated analysis and experimental verification, we found a series of biomarkers which were regulated by methylation should be potential therapeutic targets for IPF.

2016 ◽  
Vol 310 (6) ◽  
pp. F477-F491 ◽  
Jakob L. Rukov ◽  
Eva Gravesen ◽  
Maria L. Mace ◽  
Jacob Hofman-Bang ◽  
Jeppe Vinther ◽  

The development of vascular calcification (VC) in chronic uremia (CU) is a tightly regulated process controlled by factors promoting and inhibiting mineralization. Next-generation high-throughput RNA sequencing (RNA-seq) is a powerful and sensitive tool for quantitative gene expression profiling and the detection of differentially expressed genes. In the present study, we, for the first time, used RNA-seq to examine rat aorta transcriptomes from CU rats compared with control rats. Severe VC was induced in CU rats, which lead to extensive changes in the transcriptional profile. Among the 10,153 genes with an expression level of >1 reads/kilobase transcript/million mapped reads, 2,663 genes were differentially expressed with 47% upregulated genes and 53% downregulated genes in uremic rats. Significantly deregulated genes were enriched for ontologies related to the extracellular matrix, response to wounding, organic substance, and ossification. The individually affected genes were of relevance to osteogenic transformation, tissue calcification, and Wnt modulation. Downregulation of the Klotho gene in uremia is believed to be involved in the development of VC, but it is debated whether the effect is caused by circulating Klotho only or if Klotho is produced locally in the vasculature. We found that Klotho was neither expressed in the normal aorta nor calcified aorta by RNA-seq. In conclusion, we demonstrated extensive changes in the transcriptional profile of the uremic calcified aorta, which were consistent with a shift in phenotype from vascular tissue toward an osteochondrocytic transcriptome profile. Moreover, neither the normal vasculature nor calcified vasculature in CU expresses Klotho.

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Siying He ◽  
Hui Sun ◽  
Yifang Huang ◽  
Shiqi Dong ◽  
Chen Qiao ◽  

Purpose. MiRNAs have been widely analyzed in the occurrence and development of many diseases, including pterygium. This study aimed to identify the key genes and miRNAs in pterygium and to explore the underlying molecular mechanisms. Methods. MiRNA expression was initially extracted and pooled by published literature. Microarray data about differentially expressed genes was downloaded from Gene Expression Omnibus (GEO) database and analyzed with the R programming language. Functional and pathway enrichment analyses were performed using the database for Annotation, Visualization and Integrated Discovery (DAVID). The protein-protein interaction network was constructed with the STRING database. The associations between chemicals, differentially expressed miRNAs, and differentially expressed genes were predicted using the online resource. All the networks were constructed using Cytoscape. Results. We found that 35 miRNAs and 301 genes were significantly differentially expressed. Functional enrichment analysis showed that upregulated genes were significantly enriched in extracellular matrix (ECM) organization, while downregulated genes were mainly involved in cell death and apoptotic process. Finally, we concluded the chemical-gene affected network, miRNA-mRNA interacted networks, and significant pathway network. Conclusion. We identified lists of differentially expressed miRNAs and genes and their possible interaction in pterygium. The networks indicated that ECM breakdown and EMT might be two major pathophysiological mechanisms and showed the potential significance of PI3K-Akt signalling pathway. MiR-29b-3p and collagen family (COL4A1 and COL3A1) might be new treatment target in pterygium.

2020 ◽  
Sheng Chang ◽  
Yang Cao

Abstract Background: Osteosarcoma (osteogenic sarcoma, OS) is a primary cause of morbidity and mortality and is associated with poor prognosis in the field of orthopedic. Globally, rates of OS are highest among 15 to 25-year-old adolescent. However, the mechanism of gene regulation and signaling pathway is unknown. Material and Methods: GSE9508, including 34 OS samples and 5 non-malignant bone samples, was gained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were picked out by GEO2R online R soft tool. Furthermore, the protein-protein interaction (PPI) network between the DEGs was molded utilizing STRING online software. Afterward, PPI network of DEGs was constructed. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs were carried out on DAVID online tool and visualized via cytoscape software. Subsequently, module analysis of PPI was performed by using MCODE app. What’s more, prognosis-related genes were screened by using online databases including GEPIA, UALCAN and cBioPortal databases. Results: Totally, 671 DEGs were picked out, including 501 up-regulated genes and 170 down-regulated genes. Moreover, 22 hub genes were identified to be significantly expressed in PPI network (16 up-regulated and 6 down-regulated). We found that spliceosome signaling pathway may provide a potential target in OS. Furthermore, on the basis of common crucial pathway, PRPF38A and SNRPC were closely associated with spliceosome. Conclusion: This study showed that SNRPC and PRPF38A are potential biomarkers candidates for osteosarcoma.

2020 ◽  
Yun Yang ◽  
Jiao Meng Chen ◽  
Huan Huan Ding ◽  
Jing Le Zhu ◽  
Yan Hong Du

Abstract Background: Eucommia ulmoides ‘Oliver’ is an economically important tree species with highly medicinal and ecological values that is naturally distributed in China. E. ulmoides ‘Huazhong No. 12’ (H12) is the only red-leaf genotype of this species. In this study, the pigment contents of H12 and E. ulmoides ‘Huazhong No. 11’ (H11, green leaves) were determined. The differential metabolites in H12 and H11 were detected by UPLC-MS/MS, and the differentially expressed genes were screened by transcriptome. Then the key metabolites and corresponding gene regulation in anthocyanin related metabolic pathway were analyzed.Results: The chlorophyll a, chlorophyll b and carotenoid contents in H12 leaves were lower than H11, while the total anthocyanin content in H12 was 4.06 times higher than in H11. There were 96 up-regulated metabolites in H12, including anthocyanin, proanthocyanidins, flavonoid and flavonol. Among them, four differentially expressed anthocyanins were identified. A total of 8,368 differentially expressed genes were selected from transcriptome between H12 and H11. The flavone and flavonol biosynthesis pathway, anthocyanin pathway and photosynthetic pathway were analyzed. Finally, EuCHI, EuF3'H, EuF3'5'H, EuDFR and Eu3MaT1 were recommended as the key genes. The cyanidin, cyanidin 3-malonyl-glucoside and cyanidin 3, 5-glucoside were responsible for the H12 red leaves.Conclusion: This study revealed the metabolites and gene regulation of anthocyanin synthesis, and the potential function between the anthocyanin and photosynthetic gene expression in E. ulmoides red leaves. Notably, the results also provided a reference for the study of other plant leaf-coloring mechanisms.

2019 ◽  
Elena F. Boer ◽  
Hannah F. Van Hollebeke ◽  
Sungdae Park ◽  
Carlos R. Infante ◽  
Douglas B. Menke ◽  

AbstractThe tetrapod limb is a stunning example of evolutionary diversity, with dramatic variation not only among distantly related species, but also between the serially homologous forelimbs (FLs) and hindlimbs (HLs) within species. Despite this variation, highly conserved genetic and developmental programs underlie limb development and identity in all tetrapods, raising the question of how limb diversification is generated from a conserved toolkit. In some breeds of domestic pigeon, shifts in the expression of two conserved limb identity transcription factors,PITX1andTBX5, are associated with the formation of feathered HLs with partial FL identity. To determine how modulation ofPITX1andTBX5expression affects downstream gene expression, we compared the transcriptomes of embryonic limb buds from pigeons with scaled and feathered HLs. We identified a set of differentially expressed genes enriched for genes encoding transcription factors, extracellular matrix proteins, and components of developmental signaling pathways with important roles in limb development. A subset of the genes that distinguish scaled and feathered HLs are also differentially expressed between FL and scaled HL buds in pigeons, pinpointing a set of gene expression changes downstream ofPITX1andTBX5in the partial transformation from HL to FL identity. We extended our analyses by comparing pigeon limb bud transcriptomes to chicken, anole lizard, and mammalian datasets to identify deeply conservedPITX1- andTBX5-regulated components of the limb identity program. Our analyses reveal a suite of predominantly low-level gene expression changes that are conserved across amniotes to regulate the identity of morphologically distinct limbs.Summary statementIn feather-footed pigeons, mutant alleles ofPITX1andTBX5drive the partial redeployment of an evolutionarily conserved forelimb genetic program in the hindlimb.

2012 ◽  
Vol 44 (22) ◽  
pp. 1098-1106 ◽  
Mohamed T. Ghorbel ◽  
Amir Mokhtari ◽  
Maimuna Sheikh ◽  
Gianni D. Angelini ◽  
Massimo Caputo

In cyanotic patients undergoing repair of heart defects, high level of oxygen during cardiopulmonary bypass (CPB) leads to greater susceptibility to myocardial ischemia and reoxygenation injury. This study investigates the effects of controlled reoxygenation CPB on gene expression changes in cyanotic hearts of patients undergoing surgical correction of tetralogy of Fallot (TOF). We randomized 49 cyanotic TOF patients undergoing corrective cardiac surgery to receive either controlled reoxygenation or hyperoxic/standard CPB. Ventricular myocardium biopsies were obtained immediately after starting and before discontinuing CPB. Microarray analyses were performed on samples, and array results validated with real-time PCR. Gene expression profiles before and after hyperoxic/standard CPB revealed 35 differentially expressed genes with three upregulated and 32 downregulated. Upregulated genes included two E3 Ubiquitin ligases. The products of downregulated genes included intracellular signaling kinases, metabolic process proteins, and transport factors. In contrast, gene expression profiles before and after controlled reoxygenation CPB revealed only 11 differentially expressed genes with 10 upregulated including extracellular matrix proteins, transport factors, and one downregulated. The comparison of gene expression following hyperoxic/standard vs. controlled reoxygenation CPB revealed 59 differentially expressed genes, with six upregulated and 53 downregulated. Upregulated genes included PDE1A, MOSC1, and CRIP3. Downregulated genes functionally clustered into four major classes: extracellular matrix/cell adhesion, transcription, transport, and cellular metabolic process. This study provides direct evidence that hyperoxic CPB decreases the adaptation and remodeling capacity in cyanotic patients undergoing TOF repair. This simple CPB strategy of controlled reoxygenation reduced the number of genes whose expression was altered following hyperoxic/standard CPB.

Weed Science ◽  
2012 ◽  
Vol 60 (2) ◽  
pp. 158-166 ◽  
Janet Moriles ◽  
Stephanie Hansen ◽  
David P. Horvath ◽  
Graig Reicks ◽  
David E. Clay ◽  

Weed interference with crop growth is often attributed to water, nutrient, or light competition; however, specific physiological responses to these stresses are not well described. This study's objective was to compare growth, yield, and gene expression responses of corn to nitrogen (N), low light (40% shade), and weed stresses. Corn vegetative parameters from V2 to V12 stages, yield parameters, and gene expression using transcriptome (2008) and quantitative polymerase chain reaction (qPCR) (2008/09) analyses at V8 were compared among the stresses and with nonstressed corn. N stress did not affect vegetative parameters, although grain yield was reduced by 40% compared with nonstressed plants. Shade, present until V2, reduced biomass and leaf area > 50% at V2, and recovering plants remained smaller than nonstressed plants at V12. However, grain yields of shade-stressed and nonstressed plants were similar, unless shade remained until V8. Weed stress reduced corn growth and yield in 2008 when weeds remained until V6. In 2009, weed stress until V2 reduced corn vegetative growth, but yield reductions occurred only if weed stress remained until V6 or later. Principle component analysis of differentially expressed genes indicated that shade and weed stress had more similar gene expression patterns to each other than they did to nonstressed or N-stressed tissues. However, corn grown in N-stressed conditions shared 252 differentially expressed genes with weed-stressed plants. Ontologies associated with light/photosynthesis, energy conversion, and signaling were down-regulated in response to all three stresses. Shade and weed stress clustered most tightly together, based on gene expression, but shared only three ontologies, O-METHYLTRANSFERASE activity (lignification processes), POLY(U)-BINDING activity (posttranscriptional gene regulation), and stomatal movement. Based on morphologic and genomic observations, weed stress to corn was not explained by individual effects of N or light stress. Therefore, we hypothesize that these stresses share limited signaling mechanisms.

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 440.1-441
C. Dees ◽  
S. Poetter ◽  
M. Fuchs ◽  
C. Bergmann ◽  
A. E. Matei ◽  

Background:Excessive activation of fibroblasts with a TGFβ-biased gene signature and deposition of extracellular matrix are key features of fibrotic diseases. The mechanisms underlying these transcriptional changes remain poorly understood. Deregulation, mutations and malfunctions of transcriptional co-regulators, which can interact with multiple transcription factors and enable a broad-spectrum regulation of transcriptional networks, have been implicated as driving factors in a large number of diseases and pathologies.Objectives:In the present study, we aimed to analyze the role of the co-regulator Nuclear Receptor Co-Activator 3 (NCOA3) in fibroblast activation and tissue fibrosis, and to evaluate a potential interaction of NCOA3 with fibrosis-relevant transcription factors.Methods:NCOA3 was inhibited genetically by siRNA transfection and pharmacologically by the SRC3 inhibitor-2 (SI-2). We performed bulk RNASeq of human dermal fibroblasts and in silico transcription factor binding site screening of differentially expressed genes (DEGs). The interaction of NCOA3 and TGFβ-SMAD signaling was analyzed by reporter and CoIP assays.Results:The expression of NCOA3 in skin biopsies of SSc patients compared to normal controls demonstrated that SSc fibroblasts express modestly, but significantly reduced levels of NCOA3, which persisted in cultured SSc fibroblasts. Stimulation of normal fibroblasts with chronically high levels of TGFβ as they also occur in fibrotic tissue remodeling strongly decreased NCOA3 expression to a similar extent as in SSc fibroblasts. Furthermore, NCOA3 expression is also deregulated in different murine models of skin fibrosis. To investigate the functional effects of decreased NCOA3 levels, we targeted the expression of NCOA3 in normal fibroblasts. SiRNA-mediated knockdown of NCOA3 ameliorated TGFβ-induced gene expression, collagen release, myofibroblast differentiation and cell proliferation. In contrast, knockdown of NCOA3 had no effects on collagen release, expression of contractile proteins or gene expression in unstimulated fibroblasts, suggesting that NCOA3 is not required for cellular homeostasis. To characterize the molecular mechanisms, we performed RNASeq upon NCOA3 knockdown. We identified 343 significant differentially expressed genes (220 downregulated and 123 upregulated with a Benjamini-Hochberg false discovery rate FDR < 0.25 and fold change > 1.5) between TGFβ-stimulated fibroblasts with and without NCOA3 knockdown (NCOA3-DEGs) including the fibrosis-relevant genes EDNRB, COL5A3, HES1, IL11 or IL33. Functional analysis of the NCOA3-DEGs showed enrichment of pathway terms such as collagen binding and extracellular matrix organization. In silico screening of the promoters of the NCOA3-DEGs for potential transcription factor binding motifs revealed binding motifs of core transcription factors of fibroblast activation and tissue fibrosis such as SMAD2/3/4, RBPJ, ZEB1, TCF4, REL, and SNAIL2 amongst the downregulated NCOA3-DEGs. Experimental validation of our biostatistical results using SMAD3 as example demonstrated a higher percentage of NCOA3-pSMAD3 double-positive fibroblasts in skin sections of SSc patients compared to healthy controls. In addition, knockdown of NCOA3 reduced TGFβ-induced SMAD-reporter activity. Furthermore, stimulation with TGFβ increased the interaction of NCOA3 with SMAD3 as analyzed by co-immunoprecipitation. Simultaneous knockdown of NCOA3 and SMAD3 showed no additional reductions compared to the single knockdowns, suggesting that NCOA3 controls SMAD3-dependent gene transcription under fibrotic conditions. Finally, inhibition of NCOA3 showed anti-fibrotic effects in different murine models of experimental skin and lung fibrosis.Conclusion:Our findings characterize NCOA3 as regulator of multiple pro-fibrotic transcription programs. Pharmaceutical inhibition of NCOA3 might be a strategy to interfere simultaneously with several core pro-fibrotic mediators in fibrotic diseases such as SSc.Acknowledgements:We thank Lena Summa, Vladyslav Fedorchenko, Wolfgang Espach and Regina Kleinlein for excellent technical assistance.The study was funded by grants DI 1537/7-1, DI 1537/8-1, DI 1537/9-1 and -2, DI 1537/11-1, DI 1537/12-1, DI 1537/13-1, DI 1537/14-1, DI 1537/17-1, DE 2414/2-1, DE 2414/4-1, and RA 2506/3-1 of the German Research Foundation, SFB CRC1181 (project C01) and SFB TR221/ project number 324392634 (B04) of the German Research Foundation, grants J39, J40 and A64 of the IZKF in Erlangen, grant 2013.056.1 of the Wilhelm-Sander-Foundation, grants 2014_A47, 2014_A248 and 2014_A184 of the Else-Kröner-Fresenius-Foundation, grant 14-12-17-1-Bergmann of the ELAN-Foundation Erlangen, BMBF (Era-Net grant 01KT1801), MASCARA program, TP 2 and a Career Support Award of Medicine of the Ernst Jung Foundation.Disclosure of Interests:Clara Dees: None declared, Sebastian Poetter: None declared, Maximilian Fuchs: None declared, Christina Bergmann: None declared, Alexandru-Emil Matei: None declared, Andrea-Hermina Györfi: None declared, Alina Soare: None declared, Andreas Ramming: None declared, Paolo Ceppi: None declared, Georg Schett: None declared, Meik Kunz: None declared, Jörg H.W. Distler Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB

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