Meta-analysis of molecular response of kidney to ischemia reperfusion injury for the identification of new candidate genes

Abstract Background Accumulated to-date microarray data on ischemia reperfusion injury (IRI) of kidney represent a powerful source for identifying new targets and mechanisms of kidney IRI. In this study, we conducted a meta-analysis of gene expression profiles of kidney IRI in human, pig, rat, and mouse models, using a new scoring method to correct for the bias of overrepresented species. The gene expression profiles were obtained from the public repositories for 24 different models. After filtering against inclusion criteria 21 experimental settings were selected for meta-analysis and were represented by 11 rat models, 6 mouse models, and 2 models each for pig and human, with a total of 150 samples. Meta-analysis was conducted using expression-based genome-wide association study (eGWAS). The eGWAS results were corrected for a rodent species bias using a new weighted scoring algorithm, which favors genes with unidirectional change in expression in all tested species. Results Our meta-analysis corrected for a species bias, identified 46 upregulated and 1 downregulated genes, of which 26 (55%) were known to be associated with kidney IRI or kidney transplantation, including LCN2, CCL2, CXCL1, HMOX1, ICAM1, ANXA1, and TIMP1, which justified our approach. Pathway analysis of our candidates identified “Acute renal failure panel” as the most implicated pathway, which further validates our new method. Among new IRI candidates were 10 novel (<5 published reports related to kidney IRI) and 11 new candidates (0 reports related to kidney IRI) including the most prominent candidates ANXA2, CLDN4, and TYROBP. The cross-species expression pattern of these genes allowed us to generate three workable hypotheses of kidney IRI, one of which was confirmed by an additional study. Conclusions Our first in the field kidney IRI meta-analysis of 150 microarray samples, corrected for a species bias, identified 10 novel and 11 new candidate genes. Moreover, our new meta-analysis correction method improved gene candidate selection by identifying genes that are model and species independent, as a result, function of these genes can be directly extrapolated to the disease state in human and facilitate translation of potential diagnostic or therapeutic properties of these candidates to the bedside.Peer Reviewe

Meeting review: 6th International Conference on Emerging Zoonoses

The 6th International Conference on Emerging Zoonoses, held at Cancun, Mexico, February 24-27, 2011, offered 84 participants from 18 countries a snapshot of current research in numerous zoonoses caused by viruses, bacteria or prions. Co-chaired by Professors Heinz Feldmann and Jürgen Richt, the conference explored 10 topics: (1) The ecology of emerging zoonotic diseases; (2) The role of wildlife in emerging zoonoses; (3) Cross-species transmission of zoonotic pathogens;(4) Emerging and neglected influenza viruses; (5) Hemorrhagic fever viruses; (6) Emerging bacterial diseases; (7) Outbreak responses to zoonotic diseases; (8) Food-borne zoonotic diseases; (9) Prion diseases; and (10) Modeling and prediction of emergence of zoonoses. Human medicine, veterinary medicine and environmental challenges are viewed as a unity, which must be considered under the umbrella of ‘One Health’. Several presentations attempted to integrate the insights gained from field data with mathematical models in the search for effective control measures of specific zoonoses. The overriding objective of the research presentations was to create, improve and use the tools essential to address the risk of contagions in a globalized society. In seeking to fulfil this objective, a three-step approach has often been applied: (1) use cultured cells, model and natural animal hosts and human clinical models to study infection; (2) combine traditional histopathological and biochemical approaches with functional genomics, proteomics and computational biology; and (3) obtain signatures of virulence and insights into mechanisms of host defense response, immune evasion and pathogenesis. This meeting review summarizes 39 of the conference presentations and mentions briefly the 16 articles in this Special Supplement, most of which were presented at the conference in earlier versions. The full affiliations of all presenters and many colleagues have been included to facilitate further inquiries from readers

RNA-seq reveals novel transcriptome of genes and their isoforms in human pulmonary microvascular endothelial cells treated with thrombin.

The dysregulation of vascular endothelial cells by thrombin has been implicated in the development of a number of pathologic disorders such as inflammatory conditions, cancer, diabetes, coronary heart disease. However, transcriptional regulation of vascular endothelial cells by thrombin is not completely understood. In the present study, Illumina RNA-seq was used to profile the transcriptome in human pulmonary microvascular endothelial cells (HMVEC-L) treated with thrombin for 6 h to gain insight into thrombin's direct effects on the endothelial function. Out of 100 million total reads from a paired end sequencing assay, 91-94% of the reads were aligned to over 16,000 genes in the reference human genome. Thrombin upregulated 150 known genes and 480 known isoforms, and downregulated 2,190 known genes and 3,574 known isoforms by at least 2 fold. Of note, thrombin upregulated 1,775 previously unknown isoforms and downregulated 12,202 previously unknown isoforms by at least 2 fold. Many genes displayed isoform specific differential expression levels and different usage of transcriptional start sites after the thrombin treatment. The cross comparisons between our RNA-seq data and those of DNA microarray analysis of either 6 h thrombin treated HUVEC or 5 h TNFα treated HMVEC have provided a significant overlapping list of differentially expressed genes, supporting the robust utility of our dataset. Further in-depth follow-up analysis of the transcriptional regulation reported in this study may shed light on molecular pathogenic mechanisms underlying thrombin mediated endothelial dysfunction in various diseases and provide new leads of potential therapeutic targets

Additional file 2: of Identification of new biomarkers for Acute Respiratory Distress Syndrome by expression-based genome-wide association study

Table S2. Chi-square values of cross-referenced genes. Given that different microarray platforms have multiple probes for a single gene, the cross-referencing of such platforms generates numerous combinations of expression values for a given gene (32160 in this study). Chi-square value was calculated for each of these combinations and combination with the best chi-square value for a given gene was retained, which resulted in 3152 unique gene entries. These genes were linked to human genome and plotted against their location (Fig. 1). (XLS 185 kb

Additional file 1: of Identification of new biomarkers for Acute Respiratory Distress Syndrome by expression-based genome-wide association study

Table S1. Detailed representation of data obtained from GEO. ARDS gene expression submissions were retrieved from GEO using two terms “Acute lung injury” and “Lung injury”, which resulted in 23 and 25 data sets, respectively. These 48 entries were filtered down to 31 entries according to conditions described in Methods. The reason for filtering out an experiment is provided. (XLSX 16 kb

A transcription profile of HMVEC cells (Control A) for chromosome 1.

<p>The RNASeq read density plotted along chromosome 1 is shown. Average alignment was computed by igvtools. The coverage values were measured along intervals of the genome. These intervals vary in size depending on how variable the read density is for a particular genomic location. Each bar represents the log₂ frequency of reads plotted against chromosome coordinates.</p