Retinol Metabolism Pathway Research Articles

Bioinformatics identification of crucial genes and pathways associated with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Up to date, HCC pathogenesis has not been fully understood. The aim of the present study was to identify crucial genes and pathways associated with HCC by bioinformatics methods. The differentially expressed genes (DEGs) between 14 HCC tissues and corresponding non-cancerous tissues were identified using limma package. Gene Ontology (GO) and KEGG pathway enrichment analysis of DEGs were performed by clusterProfiler package. The protein–protein interaction (PPI) network of DEGs was constructed and visualized by STRING database and Cytoscape software, respectively. The crucial genes in PPI network were identified using a Cytoscape plugin, CytoNCA. Furthermore, the effect of the expression level of the crucial genes on HCC patient survival was analyzed by an interactive web-portal, UALCAN. A total of 870 DEGs including 237 up-regulated and 633 down-regulated genes were identified in HCC tissues. KEGG pathway analysis revealed that DEGs were mainly enriched in complement and coagulation cascades pathway, chemical carcinogenesis pathway, retinol metabolism pathway, fatty acid degradation pathway, and valine, leucine and isoleucine degradation pathway. PPI network analysis showed that CDK1, CCNB1, CCNB2, MAD2L1, ACACB, IGF1, TOP2A, and EHHADH were crucial genes. Survival analysis suggested that the high expression of CDK1, CCNB1, CCNB2, MAD2L1, and TOP2A significantly decreased the survival probability of HCC patients. In conclusion, the identification of the above crucial genes and pathways will not only contribute to elucidating the pathogenesis of HCC, but also provide prognostic markers and therapeutic targets for HCC.

Analysis of Time-Series Gene Expression Data to Explore Mechanisms of Chemical-Induced Hepatic Steatosis Toxicity.

Non-alcoholic fatty liver disease (NAFLD) represents a wide spectrum of disease, ranging from simple fatty liver through steatosis with inflammation and necrosis to cirrhosis. One of the most challenging problems in biomedical research and within the chemical industry is to understand the underlying mechanisms of complex disease, and complex adverse outcome pathways (AOPs). Based on a set of 28 steatotic chemicals with gene expression data measured on primary hepatocytes at three times (2, 8, and 24 h) and three doses (low, medium, and high), we identified genes and pathways, defined as molecular initiating events (MIEs) and key events (KEs) of steatosis using a combination of a time series and pathway analyses. Among the genes deregulated by these compounds, the study highlighted OSBPL9, ALDH7A1, MYADM, SLC51B, PRDX6, GPAT3, TMEM135, DLGDA5, BCO2, APO10LA, TSPAN6, NEURL1B, and DUSP1. Furthermore, pathway analysis indicated deregulation of pathways related to lipid accumulation, such as fat digestion and absorption, linoleic and linolenic acid metabolism, calcium signaling pathway, fatty acid metabolism, peroxisome, retinol metabolism, and steroid metabolic pathways in a time dependent manner. Such transcription profile analysis can help in the understanding of the steatosis evolution over time generated by chemical exposure.

Human Plasma Metabolomics Implicates Modified 9-cis-Retinoic Acid in the Phenotype of Left Main Artery Lesions in Acute ST-Segment Elevated Myocardial Infarction

The detection of left main coronary artery disease (LMCAD) is crucial before ST-segment elevated myocardial infarction (STEMI) or sudden cardiac death. The aim of this study was to identify characteristic metabolite modifications in the LMCAD phenotype, using the metabolomics technique. Metabolic profiles were generated based on ultra-performance liquid chromatography and mass spectrometry, combined with multivariate statistical analysis. Plasma samples were collected prospectively from a propensity-score matched cohort including 44 STEMI patients (22 consecutive LMCAD and 22 non-LMCAD), and 22 healthy controls. A comprehensive metabolomics data analysis was performed with Metaboanalyst 3.0 version. The retinol metabolism pathway was shown to have the strongest discriminative power for the LMCAD phenotype. According to biomarker analysis through receiver-operating characteristic curves, 9-cis-retinoic acid (9cRA) dominated the first page of biomarkers, with area under the curve (AUC) value 0.888. Next highest were a biomarker panel consisting of 9cRA, dehydrophytosphingosine, 1H-Indole-3-carboxaldehyde, and another seven variants of lysophosphatidylcholines, exhibiting the highest AUC (0.933). These novel data propose that the retinol metabolism pathway was the strongest differential pathway for the LMCAD phenotype. 9cRA was the most critical biomarker of LMCAD, and a ten-metabolite plasma biomarker panel, in which 9cRA remained the weightiest, may help develop a potent predictive model for LMCAD in clinic.

MicroRNA-223 Suppresses Osteoblast Differentiation by Inhibiting DHRS3

Background/Aims: In this study, we aimed to use bioinformatics tools to identify the specific miRNAs and mRNAs involved in osteogenic differentiation and to further explore the way in which miRNA regulates osteogenic differentiation. Methods: The microarray GSE80614, which includes data from 3 human mesenchymal stromal cells (hMSCs) and 3 hMSCs after 72 hours (hr) of osteogenic differentiation, was used to screen for differentially expressed mRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of these mRNAs were conducted using Gene Set Enrichment Analysis (GSEA). Then, the miRanda website was employed to detect the binding sites of DHRS3. In vitro experiments, including RT-PCR and western blotting, were used to detect miR-233 and DHRS3 expression levels 7 and 14 days (d) after the induction of osteogenic differentiation using human bone marrow-derived mesenchymal stem cells (hBMSCs). The target relationship between miR-223 and DHRS3 was confirmed by a dual luciferase assay. ALP (alkaline phosphatase) staining, ARS (Alizarin Red S) staining and western blotting (Runx2, OPN, OCN) were used to detect the level of osteogenic differentiation after transfection with miR-223 mimics and DHRS3 cDNA. Results: In this study, 127 mRNAs differentially expressed during osteogenic differentiation were identified in GSE80614. GO term and KEGG pathway enrichment analyses found that the retinol metabolism pathway was activated during osteogenic differentiation and that DHRS3, which is involved in the pathway, was upregulated. During osteogenic differentiation in hBMSCs, miR-223 was gradually downregulated, while DHRS3 was upregulated. After 14 days of osteogenic differentiation, ALP and ARS staining assay results showed strong ALP activity and extracellular matrix calcification with the inhibition of miR-223 or the overexpression of DHRS3. Furthermore, the expression levels of Runx2, OPN, and OCN were upregulated with the knockdown of miR-223 or the overexpression of DHRS3, while the simultaneous transfection of a miR-223 agomir and DHRS3 cDNA resulted in no significant difference from the negative control (NC) group. Conclusion: The inhibition of miR-223 promotes the osteogenic differentiation of hBMSCs via the upregulation of DHRS3.

Transcriptome analysis reveals a positive role for nerve growth factor in retinol metabolism in primary rat hepatocytes

Up-regulation of nerve growth factor (NGF) in parenchymal hepatocytes with cholestatic injury has been previously demonstrated to exert hepatoprotective effects in an autocrine manner; however, the overall impact of NGF up-regulation remains elusive. This study aimed to profile the effects of exogenous NGF on cultured primary rat hepatocytes using transcriptome analysis. Total RNA was isolated from hepatocytes with and without 24 h of NGF exposure, and subjected to RNA enrichment by PCR and RNA sequencing procedures. Comparison of transcriptome profiles between control and NGF-stimulated hepatocytes demonstrated that NGF significantly up-regulated 10 genes and down-regulated 23 genes in hepatocytes. Subsequent KEGG pathway enrichment analysis indicated that NGF significantly affected the retinol metabolism pathway via increased retinol dehydrogenase 16 (RDH16) expression. In a mouse model of bile duct ligation-induced cholestatic liver injury, NGF supplementation significantly enhanced RDH16 expression, whereas administration of anti-NGF neutralizing antibodies prominently decreased RDH16 expression in cholestatic livers, supporting the positive role of NGF in the regulation of RDH16 in diseased livers. In vitro study further demonstrated that NGF triggered de novo synthesis of RDH16 in primary rat hepatocytes, mainly through an NF-κB signaling pathway. In conclusion, this study demonstrates the up-regulation of RDH16 by NGF in cultured rat hepatocytes and mouse cholestatic livers, and provides novel insights on the mechanistic role of NGF in the retinol metabolism of livers.

Chinese herbal formula Fuzheng Huayu alleviates CCl4-induced liver fibrosis in rats: a transcriptomic and proteomic analysis.

Liver fibrosis is a consequence of chronic liver disease that can progress to liver cirrhosis or even hepatocarcinoma. Fuzheng Huayu (FZHY), a Chinese herbal formula, has been shown to exert anti-fibrotic effects. To better understand the molecular mechanisms underlying the anti-fibrotic effects of FZHY, we analyzed transcriptomic and proteomic combination profiles in CCl4-induced liver fibrosis in rats, which were treated with extracted FZHY powder (0.35 g·kg-1·d-1, ig) for 3 weeks. We showed that FZHY administration significantly improved liver function, alleviated hepatic inflammatory and fibrotic changes, and decreased the hydroxyproline content in the livers of CCl4-treated rats. When their liver tissues were examined using microarray and iTRAQ, we found 255 differentially expressed genes (fold change ≥1.5, P<0.05) and 499 differentially expressed proteins (fold change ≥1.2, P<0.05) in the FZHY and model groups. Functional annotation with DAVID (The Database for Annotation, Visualization and Integrated Discovery) showed that 15 enriched gene ontology terms, including drug metabolic process, response to extracellular stimulus, response to vitamins, arachidonic acid metabolic process, response to wounding, and oxidation reduction might be involved in the anti-fibrotic effects of FZHY; whereas KEGG pathway analysis revealed that eight enriched pathways, including arachidonic acid metabolism, retinol metabolism, metabolism of xenobiotics by cytochrome P450, and drug metabolism might also be involved. Moreover, the protein-protein interaction network demonstrated that 10 core genes/proteins overlapped, with Ugt2a3, Cyp2b1 and Cyp3a18 in retinol metabolism pathway overlapped to a higher degree. Compared to the model rats, the livers of FZHY-treated rats had significantly higher mRNA and protein expression levels of Ugt2a3, Cyp2b1 and Cyp3a18. Furthermore, the concentration of retinoic acid was significantly higher in the FZHY-treated rats compared with the model rats. The results suggest that the anti-fibrotic effects of FZHY emerge through multiple targets, multiple functions, and multiple pathways, including FZHY-regulated retinol metabolism, xenobiotic metabolism by cytochrome P450, and drug metabolism through up-regulated Ugt2a3, Cyp2b1, and Cyp3a18. These genes may play important anti-fibrotic roles in FZHY-treated rats.

Transcriptomic Analysis of Thalidomide Challenged Chick Embryo Suggests Possible Link between Impaired Vasculogenesis and Defective Organogenesis.

Since the conception of thalidomide as a teratogen, approximately 30 hypotheses have been put forward to explain the developmental toxicity of the molecule. However, no systems biology approach has been taken to understand the phenomena yet. The proposed work was aimed to explore the mechanism of thalidomide toxicity in developing chick embryo in the context of transcriptomics by using genome wide RNA sequencing data. In this study, we challenged the developing embryo at the stage of blood island formations (HH8), which is the most vulnerable stage for thalidomide-induced deformities. We observed that thalidomide affected the early vasculogenesis through interfering with the blood island formation extending the effect to organogenesis. The transcriptome analyses of the embryos collected on sixth day of incubation showed that liver, eye, and blood tissue associated genes were down regulated due to thalidomide treatment. The conserved gene coexpression module also indicated that the genes involved in lens development were heavily affected. Further, the Gene Ontology analysis explored that the pathways of eye development, retinol metabolism, and cartilage development were dampened, consistent with the observed deformities of various organs. The study concludes that thalidomide exerts its toxic teratogenic effects through interfering with early extra-embryonic vasculogenesis and ultimately gives an erroneous transcriptomic pattern to organogenesis.

A Preliminary Study on the Pattern, the Physiological Bases and the Molecular Mechanism of the Adductor Muscle Scar Pigmentation in Pacific Oyster Crassostrea gigas.

The melanin pigmentation of the adductor muscle scar and the outer surface of the shell are among attractive features and their pigmentation patterns and mechanism still remains unknown in the Pacific oyster Crassostrea gigas. To study these pigmentation patterns, the colors of the adductor muscle scar vs. the outer surface of the shell on the same side were compared. No relevance was found between the colors of the adductor muscle scars and the corresponding outer surface of the shells, suggesting that their pigmentation processes were independent. Interestingly, a relationship between the color of the adductor muscle scars and the dried soft-body weight of Pacific oysters was found, which could be explained by the high hydroxyl free radical scavenging capacity of the muscle attached to the black adductor muscle scar. After the transcriptomes of pigmented and unpigmented adductor muscles and mantles were studied by RNAseq and compared, it was found that the retinol metabolism pathway were likely to be involved in melanin deposition on the adductor muscle scar and the outer surface of the shell, and that the different members of the tyrosinase or Cytochrome P450 gene families could play a role in the independent pigmentation of different organs.

Transcriptome analysis of comb and testis from Rose-comb Silky chicken (R1/R1) and Beijing Fatty wild type chicken (r/r)

Rose-comb was one of the chicken comb-variants first used by Bateson and Punnet in 1902 to demonstrate Mendelian inheritance in animals. Rose-comb is a monogenic trait that has been widely described in chickens. It is caused by a large structural rearrangement that leads to mis-expression of transcription factor MNR2 on chromosome 7. Rose-comb has pleiotropic effects in homozygous roosters, which is associated with poor sperm mobility. It was postulated that this is caused by the disruption of the CCDC108 gene located at the distal inversion breakpoint. In this study, we did the transcriptional profiling of combs and testes from Rose-comb Silky (RS) (R1/R1) and Beijing Fatty (BF) wild type chickens (r/r) using RNA-seq. We obtained 68,694,797 unique mapped reads and over 80% of the chicken genes were covered for each sample. In combs, we found that differentially expressed genes (DEGs) were significantly enriched in the retinol metabolism (RPE65, CYP26A1, and CYP26C1) and hedgehog-signaling pathway (PTCH1, GLI1, and HHIP), while genes related to cell differentiation and morphogenesis were down-regulated in R1/R1 chickens, suggesting that the transient expression of MNR2 might affect the expression of these genes and influence the development of comb tissue. For testes, DEGs were significantly enriched in the GO terms of binding activates and mitochondrial oxidation-reduction reactions. Our results suggested that the CCDC108 might be functionally related with mitochondrial oxidation-reduction reactions and caused subfertility of roosters. Compared with the genome average, the degree of expression variations within the inversion region did not show significant differences. However, DEGs near the breakpoints showed greater expression variance. Our results demonstrated that the large-scale rearrangements affected the gene expression only around the breakpoint in this case.

RNA-sequencing and pathway analysis reveal alteration of hepatic steroid biosynthesis and retinol metabolism by tributyltin exposure in male rare minnow (Gobiocypris rarus)

Tributyltin (TBT) is widely spread in aquatic ecosystems. Although adverse effects of TBT on reproduction and lipogenesis are observed in fishes, the underlying mechanisms, especially in livers, are still scarce and inconclusive. Thus, RNA-sequencing runs were performed on the hepatic libraries of adult male rare minnow (Gobiocypris rarus) after TBT exposure for 60d. After differentially expressed genes were identified, enrichment analysis and validation by quantitative real-time PCR were conducted. The results showed that TBT up-regulated the profile of hepatic genes in the steroid biosynthesis pathway and down-regulated the profile of hepatic genes in the retinol metabolism pathway. In the hepatic steroid biosynthesis pathway, TBT might induce biosynthesis of cholesterol, which could affect the bioavailability of steroid hormones. More important, 3beta-hydroxysteroid 3-dehydrogenase, a key enzyme in the biosynthesis of all active steroid hormones, was up-regulated by TBT exposure. In the hepatic retinol metabolism pathway, TBT impaired retinoic acid homeostasis which plays essential roles in both reproduction and lipogenesis. The results of two pathways offered new mechanisms underlying the toxicology of TBT and represented a starting point from which detailed mechanistic links should be explored.

Identification of key pathways and genes in colorectal cancer using bioinformatics analysis.

Colorectal cancer (CRC) is the most common malignant tumor of digestive system. The aim of this study was to identify gene signatures during CRC and uncover their potential mechanisms. The gene expression profiles of GSE21815 were downloaded from GEO database. The GSE21815 dataset contained 141 samples, including 132 CRC and 9 normal colon epitheliums. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed, and protein-protein interaction (PPI) network of the differentially expressed genes (DEGs) was constructed by Cytoscape software. In total, 3500 DEGs were identified in CRC, including 1370 up-regulated genes and 2130 down-regulated genes. GO analysis results showed that up-regulated DEGs were significantly enriched in biological processes (BP), including cell cycle, cell division, and cell proliferation; the down-regulated DEGs were significantly enriched in biological processes, including immune response, intracellular signaling cascade and defense response. KEGG pathway analysis showed the up-regulated DEGs were enriched in cell cycle and DNA replication, while the down-regulated DEGs were enriched in drug metabolism, metabolism of xenobiotics by cytochrome P450, and retinol metabolism pathways. The top 10 hub genes, GNG2, AGT, SAA1, ADCY5, LPAR1, NMU, IL8, CXCL12, GNAI1, and CCR2 were identified from the PPI network, and sub-networks revealed these genes were involved in significant pathways, including G protein-coupled receptors signaling pathway, gastrin-CREB signaling pathway via PKC and MAPK, and extracellular matrix organization. In conclusion, the present study indicated that the identified DEGs and hub genes promote our understanding of the molecular mechanisms underlying the development of CRC, and might be used as molecular targets and diagnostic biomarkers for the treatment of CRC.

Differential gene expression in the duodenum, jejunum and ileum among crossbred beef steers with divergent gain and feed intake phenotypes.

Small intestine mass and cellularity were previously associated with cattle feed efficiency. The small intestine is responsible for the digestion of nutrients and absorption of fatty acids, amino acids and carbohydrates, and it contributes to the overall feed efficiency of cattle. The objective of this study was to evaluate transcriptome differences among the small intestine from cattle with divergent gain and feed intake. Animals most divergent from the bivariate mean in each of the four phenotypic Cartesian quadrants for gain×intake were selected, and the transcriptomes of duodenum, jejunum and ileum were evaluated. Gene expression analyses were performed comparing high gain vs. low gain animals, high intake vs. low intake animals and each of the phenotypic quadrants to all other groups. Genes differentially expressed within the high gain-low intake and low gain-high intake groups of animals included those involved in immune function and inflammation in all small intestine sections. The high gain-high intake group differed from the high gain-low intake group by immune response genes in all sections of the small intestine. In all sections of small intestine, animals with low gain-low intake displayed greater abundance of heat-shock genes compared to other groups. Several over-represented pathways were identified. These include the antigen-processing/presentation pathway in high gain animals and PPAR signaling, starch/sucrose metabolism, retinol metabolism and melatonin degradation pathways in the high intake animals. Genes with functions in immune response, inflammation, stress response, influenza pathogenesis and melatonin degradation pathways may have a relationship with gain and intake in beef steers.

Qishen Yiqi Drop Pill improves cardiac function after myocardial ischemia.

Myocardial ischemia (MI) is one of the leading causes of death, while Qishen Yiqi Drop Pill (QYDP) is a representative traditional Chinese medicine to treat this disease. Unveiling the pharmacological mechanism of QYDP will provide a great opportunity to promote the development of novel drugs to treat MI. 64 male Sprague-Dawley (SD) rats were divided into four groups: MI model group, sham operation group, QYDP treatment group and Fosinopril treatment group. Echocardiography results showed that QYDP exhibited significantly larger LV end-diastolic dimension (LVEDd) and LV end-systolic dimension (LVEDs), compared with the MI model group, indicating the improved cardiac function by QYDP. 1H-NMR based metabonomics further identify 9 significantly changed metabolites in the QYDP treatment group, and the QYDP-related proteins based on the protein-metabolite interaction networks and the corresponding pathways were explored, involving the pyruvate metabolism pathway, the retinol metabolism pathway, the tyrosine metabolism pathway and the purine metabolism pathway, suggesting that QYDP was closely associated with blood circulation. ELISA tests were further employed to identify NO synthase (iNOS) and cathepsin K (CTSK) in the networks. For the first time, our work combined experimental and computational methods to study the mechanism of the formula of traditional Chinese medicine.

The landscape of copy number variations in Finnish families with autism spectrum disorders.

Rare de novo and inherited copy number variations (CNVs) have been implicated in autism spectrum disorder (ASD) risk. However, the genetic underpinnings of ASD remain unknown in more than 80% of cases. Therefore, identification of novel candidate genes and corroboration of known candidate genes may broaden the horizons of determining genetic risk alleles, and subsequent development of diagnostic testing. Here, using genotyping arrays, we characterized the genetic architecture of rare CNVs (<1% frequency) in a Finnish case-control dataset. Unsurprisingly, ASD cases harbored a significant excess of rare, large (>1 Mb) CNVs and rare, exonic CNVs. The exonic rare de novo CNV rate (∼22.5%) seemed higher compared to previous reports. We identified several CNVs in well-known ASD regions including GSTM1-5, DISC1, FHIT, RBFOX1, CHRNA7, 15q11.2, 15q13.2-q13.3, 17q12, and 22q11.21. Additionally, several novel candidate genes (BDKRB1, BDKRB2, AP2M1, SPTA1, PTH1R, CYP2E1, PLCD3, F2RL1, UQCRC2, LILRB3, RPS9, and COL11A2) were identified through gene prioritization. The majority of these genes belong to neuroactive ligand-receptor interaction pathways, and calcium signaling pathways, thus suggesting that a subset of these novel candidate genes may contribute to ASD risk. Furthermore, several metabolic pathways like caffeine metabolism, drug metabolism, retinol metabolism, and calcium-signaling pathway were found to be affected by the rare exonic ASD CNVs. Additionally, biological processes such as bradykinin receptor activity, endoderm formation and development, and oxidoreductase activity were enriched among the rare exonic ASD CNVs. Overall, our findings may add data about new genes and pathways that contribute to the genetic architecture of ASD.

Latent Pathways Identification by Microarray Expression Profiles in Thyroid-Associated Ophthalmopathy Patients.

This study aimed to screen potential genes related to thyroid-associated ophthalmopathy (TAO) and get a further understanding about the pathogenesis of this disease. GSE9340 was downloaded from Gene Expression Omnibus, including eight thyroid tissue samples from hyperthyroid patients without TAO and ten ones from hyperthyroid patients with TAO. The differentially expressed genes (DEGs) were identified by the linear models for microarray data package. And their potential functions were predicted by Gene Ontology (GO) and pathway enrichment analyses. Furthermore, protein-protein interaction (PPI) was obtained from the Search Tool for the Retrieval of Interacting Genes database, and the PPI network was visualized with Cytoscape. Then, module analysis was performed by the Molecular Complex Detection analysis. Additionally, the potential pathway interactions were identified by Latent Pathway Identification Analysis. Totally, 511 upregulated and 507 downregulated DEGs in TAO were screened. Some DEGs (e.g., UBE2C) were related to cell cycle, and DEGs encoding proteasome (e.g., PSMA1, PSMC5, PSMC4, and PSMD1) were related to negative regulation of ubiquitin-protein ligase activity. Several upregulated DEGs encoding signal recognition particle (e.g., SRP14, SRP54, and SRP9) were found to be enriched in protein export pathway. Furthermore, some pathways (e.g., ribosome and protein export) had interactions. The DEGs related to cell cycle (e.g., UBE2C), DEGs encoding proteasome (e.g., PSMA1, PSMC5, PSMC4, and PSMD1) and signal recognition particle (e.g., SRP14, SRP54, and SRP9), as well as pathways of ribosome, protein export and retinol metabolism, might play key roles in the development of TAO.

The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region.

BackgroundRecent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression.MethodsWe examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study.ResultsWe found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved.ConclusionThese results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0094-0) contains supplementary material, which is available to authorized users.

Systematic toxicity mechanism analysis of proton pump inhibitors: an in silico study.

Proton pump inhibitors (PPIs) are extensively used for the treatment of gastric acid-related disorders. PPIs appear to be well tolerated and almost have no short-term side effects. However, the clinical adverse reactions of long-term PPI usage are increasingly reported in recent years. So far, there is no study that elucidates the side effect mechanisms of PPIs comprehensively and systematically. In this study, a well-defined small molecule perturbed microarray data set of 344 compounds and 1695 samples was analyzed. With this high-throughput data set, a new index (Identity, I) was designed to identify PPI-specific differentially expressed genes. Results indicated that (1) up-regulated genes, such as RETSAT, CYP1A1, CYP1A2, and UGT, enhanced vitamin A's metabolism processes in the cellular retinol metabolism pathway; and that (2) down-regulated genes, such as C1QA, C1QC, C4BPA, C4BPB, CFI, and SERPING1, enriched in the complement and coagulation cascades pathway. In addition, strong association was observed between these PPI-specific differentially expressed genes and the reported side effects of PPIs by the gene-disease association network analysis. One potential toxicity mechanism of PPIs as suggested from this systematic PPI-specific gene expression analysis is that PPIs are enriched in acidic organelles where they are activated and inhibit V-ATPases and acid hydrolases, and consequently block the pathways of antigen presentation, the synthesis and secretion of cytokines, and complement component proteins and coagulation factors. The strategies developed in this work could be extended to studies on other drugs.

Study on the regulatory mechanism of the lipid metabolism pathways during chicken male germ cell differentiation based on RNA-seq.

Here, we explore the regulatory mechanism of lipid metabolic signaling pathways and related genes during differentiation of male germ cells in chickens, with the hope that better understanding of these pathways may improve in vitro induction. Fluorescence-activated cell sorting was used to obtain highly purified cultures of embryonic stem cells (ESCs), primitive germ cells (PGCs), and spermatogonial stem cells (SSCs). The total RNA was then extracted from each type of cell. High-throughput analysis methods (RNA-seq) were used to sequence the transcriptome of these cells. Gene Ontology (GO) analysis and the KEGG database were used to identify lipid metabolism pathways and related genes. Retinoic acid (RA), the end-product of the retinol metabolism pathway, induced in vitro differentiation of ESC into male germ cells. Quantitative real-time PCR (qRT-PCR) was used to detect changes in the expression of the genes involved in the retinol metabolic pathways. From the results of RNA-seq and the database analyses, we concluded that there are 328 genes in 27 lipid metabolic pathways continuously involved in lipid metabolism during the differentiation of ESC into SSC in vivo, including retinol metabolism. Alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 1 family member A1 (ALDH1A1) are involved in RA synthesis in the cell. ADH5 was specifically expressed in PGC in our experiments and aldehyde dehydrogenase 1 family member A1 (ALDH1A1) persistently increased throughout development. CYP26b1, a member of the cytochrome P450 superfamily, is involved in the degradation of RA. Expression of CYP26b1, in contrast, decreased throughout development. Exogenous RA in the culture medium induced differentiation of ESC to SSC-like cells. The expression patterns of ADH5, ALDH1A1, and CYP26b1 were consistent with RNA-seq results. We conclude that the retinol metabolism pathway plays an important role in the process of chicken male germ cell differentiation.

Gene expression profiling of human alveolar epithelial cells (A549 cells) exposed to atmospheric particulate matter 2.5 (PM2.5) collected from Seoul, Korea

Many epidemiological and in vitro studies have shown that particulate matter 2.5 (PM2.5) is associated with adverse health effects in humans, especially respiratory morbidity and mortality1–3. While the mechanisms for these effects have been vigorously investigated for many years, they still remain uncertain. In previous studies, we collected PM2.5 samples in Seoul, Korea, where pollution results from a high level of automobile traffic, and analyzed the chemical composition of PM2.5. In the present study, we used gene expression profiling and gene ontology (GO) analysis to identify the gene expression changes in A549 human alveolar epithelial cells induced by exposure to water and organic extracts of PM2.5 (W-PM2.5 and O-PM2.5) in order to evaluate the adverse health effects of PM2.5. Transcriptomic profiling indicates that the O-PM2.5 exposure group was more sensitive in gene alterations than the W-PM2.5 exposure group. Through analysis of gene expression profiles, we identified 149 W-PM2.5-specific genes and 516 O-PM2.5-specific genes, as well as 173 commonly expressed genes in both the W-PM2.5 and O-PM2.5 exposure groups. After gene ontology (GO) analysis on the O-PM2.5-specific genes, we determined several key pathways that are known to be related to increasing pulmonary toxicity, such as immune response, regulation of inflammatory response, metabolism of xenobiotics by cytochrome P450, and retinol metabolism. However, we did not find the pulmonary toxicity-related pathways through GO analysis on the W-PM2.5-specific genes. In addition, 173 commonly expressed genes are involved in tyrosine catabolic process, retinol metabolism pathway, and steroid hormone biosynthesis — all of which are known to induce adverse health effects. In conclusion, this report describes changes in gene expression profiles in an in vitro respiratory system in response to exposure to PM2.5 water and organic extracts and relates these gene expression changes to pulmonary toxicity related pathways. This experiment adds to the understanding of how cells respond to PM2.5 exposure through transcriptional regulation.

Light perception in brittle stars: detection of the molecular actors

Event Abstract Back to Event Light perception in brittle stars: detection of the molecular actors Jerome Delroisse1*, Jérôme Mallefet2 and Patrick Flammang1 1 University of Mons, Marine Biology Organisms & Biomimetics, Belgium 2 University of Louvain-La-Neuve, Marine Biology, Belgium Echinoderm photoreception is usually considered as enigmatic because of the lack of eyes in most of the species. Although a diffuse dermal and/or neural light sense has been described in some echinoderms (1), in sea urchins and sea stars photoreceptor cells expressing opsins are localized in specialized organs: the tube feet and the optic cushions on the arm tip, respectively (2,3,4). However, opsins are also expressed in the aboral integument of sea urchins and sea stars, indicating that light perception is certainly a multi-component process (5). Numerous brittle stars are described as light sensitive (6) though almost nothing is known about photoreception in the class Ophiuroidea. Lens-like arm plates were identified in Ophiocoma wendtii and, together with the underlying photoreceptors, could constitute a new type of compound eye (7,8). In the European brittle star Amphiura filiformis, light perception is unequivocal and allows the animal to adapt its feeding activity to the day/night cycle (9,10). This species could also use photoreceptors to perceive its own bioluminescence. Light perception at the level of bioluminescent organs has already been described for a cephalopod (11) and a ctenophore (12) and could also occur in brittle stars. Transcriptome profiling in A. filiformis indicate the expression of both opsins and cryptochrome. If cryptochromes are considered as components of the circadian clock that control daily rhythms (13), opsins are the main actors of vision in metazoans (14). A. filiformis is characterized by the expression of two opsin mRNAs, which were mainly detected in regenerating arms. Phylogenetic analysis revealed one Go-opsin and one R-opsin. The retinol metabolism pathway needed for the synthesis of the opsin light sensitive chromophore was also retrieved in the transcriptome. Finally, several drosophila-like and mammalian-like phototransduction actors were identified in arm tissues, confirming the implication of an opsin-based system. These opsins are probably involved in ambient light perception and also, possibly, in bioluminescence perception. A cryptochrome-mediated process could secondarily complete the role of the opsins or at least be linked to the day/night rhythm perception.