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The Glomerular Transcriptome and a Predicted Protein–Protein Interaction Network

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The Glomerular Transcriptome and a Predicted Protein–Protein Interaction Network BASIC RESEARCH www.jasn.org The Glomerular Transcriptome and a Predicted Protein–Protein Interaction Network Liqun He,* Ying Sun,* Minoru Takemoto,* Jenny Norlin,* Karl Tryggvason,* Tore Samuelsson,† and Christer Betsholtz*‡ *Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, and ‡Department of Medicine, Karolinska Institutet, Stockholm, and †Department of Medical Biochemistry, Go¨teborg University, Go¨teborg, Sweden ABSTRACT To increase our understanding of the molecular composition of the kidney glomerulus, we performed a meta-analysis of available glomerular transcriptional profiles made from mouse and man using five different methodologies. We generated a combined catalogue of glomerulus-enriched genes that emerged from these different sources and then used this to construct a predicted protein–protein interaction network in the glomerulus (GlomNet). The combined glomerulus-enriched gene catalogue provides the most comprehensive picture of the molecular composition of the glomerulus currently available, and GlomNet contributes an integrative systems biology approach to the understanding of glomerular signaling networks that operate during development, function, and disease. J Am Soc Nephrol 19: 260–268, 2008. doi: 10.1681/ASN.2007050588 Many kidney diseases and, importantly, approxi- nins have been shown to be mutated in Alport syn- mately two thirds of all cases of ESRD originate with drome and Pierson congenital nephrotic syndromes, glomerular disease. Most cases of glomerular disease respectively.11,12 Genetic studies in mice have further are caused by systemic disorders (e.g., diabetes, hyper- revealed genes and proteins of importance for glomer- tension, lupus, obesity) for which the molecular ulus development and function, such as podoca- pathogeneses of the glomerular complications are un- lyxin,13 CD2AP,14 NEPH1,15 FAT1,16 forkhead box known. Our understanding of glomerular diseases is C2,17 transcription factor 21 (Pod1),18 protein ty- limited to a few monogenic disorders for which mu- rosine phosphatase receptor type O (GLEPP1) and tations have been identified in genes encoding glo- synaptopodin.19,20 merular proteins, such as components of the glomer- It is possible that some of these genes and pro- ular basement membrane or the podocyte filtration teins are targeted also in the common glomerular slits.1–4 These proteins are specifically, or particularly disorders triggered by systemic disease. It can be strongly, expressed in podocytes. Examples include anticipated, however, that the identification of nephrin, which was identified through its mutation in familiar nephrotic syndrome of the Finnish type,5 podocin, which is mutated in steroid-resistant ne- Received May 21, 2007. Accepted August 15, 2007. phrotic syndrome,6 and ␣-actinin-4, which is mutated Published online ahead of print. Publication date available at in familial FSGS.7 In addition, mutations in the tran- www.jasn.org. scription factors WT1 and LMX1B, which are ex- M.T.’s current affiliation is Department of Clinical Cell Biology and pressed selectively but not exclusively in podocytes, Medicine, Chiba University, Chuo-ku, Japan. lead to glomerular disorders in the context of more Correspondence: Dr. Christer Betsholtz, Department of Medi- complex syndromes referred to as nail-patella, Denys- cine, Karolinska Institutet, SE 171 77, Stockholm, Sweden. Phone: ϩ46-8-52487960; Fax: ϩ46-8-313445; E-mail: christer. 8–10 Drash, or Frasier syndromes, respectively. Finally, [email protected] glomerular basement membrane collagens and lami- Copyright © 2008 by the American Society of Nephrology 260 ISSN : 1046-6673/1902-260 J Am Soc Nephrol 19: 260–268, 2008 www.jasn.org BASIC RESEARCH additional genes and proteins with glomerulus-specific ex- we predicted a protein–protein interaction network in the pression will contribute further important information glomerulus (GlomNet). We propose that the updated cata- about glomerulus development, function, and disease. Im- logue of glomerular transcripts together with GlomNet will portantly, the identification of larger pathways and net- facilitate the search for new genes/proteins and molecular works of genes and proteins in the glomerulus would most pathways operating in glomerular assembly, physiology, likely facilitate the analysis of glomerular disease progres- and pathology. sion and help to unravel mechanisms operating in the com- mon glomerular diseases of systemic origin. So far, a few RESULTS efforts to map transcriptional profiles in glomeruli have been reported, each being successful in identifying limited Glomerulus-Enriched Gene Catalogue subsets of glomerular markers but each also suffering from We summarized and combined the results from five different limitations in scale and technology.17,21–23 Our own two expression-profiling platforms (Tables 1 and 2), four of which previous studies were based on large-scale sequencing of were previously published. These data sets include a mouse mouse glomerulus expressed sequence tag (EST) libraries. kidney EST library comparison,21 a mouse “GlomChip” cDNA By comparing mouse glomerulus EST libraries with whole- microarray profiling,17 a human SAGE profiling,23 a human kidney EST libraries, we found almost 500 glomerulus-en- Stanford cDNA microarray profiling,22 and a newly added riched genes.21 We also used mouse glomerulus cDNA mi- mouse Affymetrix Genome 430 2.0 Array profiling. croarrays (GlomChip) to identify approximately 300 Our own two previous studies compared gene expression glomerulus-enriched genes.17 In two other large-scale tran- profiles in glomerulus with whole kidney or nonglomerular scriptional profiling studies, human glomeruli and other kidney tissue.17,21 In the EST analysis,21 497 mouse UniGene nephron segments were microdissected and analyzed by clusters identified as glomerulus-enriched were mapped to 373 cDNA microarray technology,22 or serial analysis of gene homologous human Entrez genes (NCIB Entrez Gene data- expression (SAGE).23 base, http://www.ncbi.nlm.nih.gov/sites/entrez?cmdϭsearch As a result of the incomplete and only partially overlap- &dbϭgene). From the GlomChip profiling,17 357 mouse genes ping information derived from different species and differ- identified as glomerulus-enriched were mapped to 326 homol- ent technical platforms, genome-scan and glomerulus dis- ogous human Entrez genes. ease gene-hunting projects suffer from the lack of a The SAGE profiling of human kidney identified 229 tags comprehensive source of basic information about the glo- with higher levels in the glomerulus than in three other merular transcriptome. To facilitate the search for new nephron portions.23 They were mapped to 153 human Entrez causes of monogenic glomerular disorders and to help iden- genes. tify molecular pathways and networks involved in the The Stanford cDNA microarray analysis of human kid- pathogenesis of common glomerular diseases, we combined ney identified 196 cDNA clones that were predominantly published and newly produced data in a meta-analysis of the expressed in the glomerulus compared with other parts of glomerular transcriptome. On the basis of this analysis and the nephron.22 They were mapped to 102 human Entrez with the aid of other available data and bioinformatics tools, genes. Table 1. Summary of the characteristics of the five methodsa Total Glomerulus- Method Species Features on Enriched Genes Selection Criteria the Platform Reported EST libraries Mouse 13,368 EST 497 P Ͻ 0.05, more than three-fold comparison difference with whole kidney tissue GlomChip profiling Mouse 18,496 probes 357 P Ͻ 0.05, more than two-fold difference with nonglomerular kidney tissue Affymetrix profiling Mouse 45,101 probes 1013 P Ͻ 0.05, more than two-fold difference with nonglomerular kidney tissue SAGE profiling Human ϳ50,000 tags 153 P Ͻ 0.01, seven-fold or more difference with at least three nephron libraries Stanford cDNA Human 41,859 probes 102 Cluster analysis, genes predominantly microarray expressed in glomeruli than others profiling aSpecies column shows the RNA sample source for the methods. For each method, total features on the platforms, number of genes identified (mouse/human), and the selection criteria for glomerulus-enriched genes are listed. J Am Soc Nephrol 19: 260–268, 2008 Systems Biology of the Glomerulus 261 BASIC RESEARCH www.jasn.org Table 2. Summary of the statistics of the five methodsa Glomerulus-Enriched Literature HPA Confirmed Method Gene (Human) Confirmed (n [%]) (n [%]) EST libraries Comparison 373 73 (19.6) 17 (4.6) GlomChip profiling 326 63 (19.3) 19 (5.8) Affymetrix profiling 914 84 (9.2) 32 (3.5) SAGE profiling 153 37 (24.2) 12 (7.8) Stanford cDNA microarray profiling 102 16 (15.7) 3 (2.9) aThe numbers of glomerulus-enriched genes were counted as human Entrez genes or corresponding human homologous genes. Numbers of literature- and HPA-confirmed genes were also counted. The percentages in the parentheses show the percentage of the corresponding number among the total gene number. We also compared the gene expression profile of mouse genes thus showed surprisingly limited overlap. Also, each ap- glomeruli with nonglomerulus kidney tissue on Affymetrix proach identified a unique set of genes that were not identified by Mouse Genome 430 2.0 Arrays. Pure preparations of glomeruli any of the other methods. were isolated from newborn mice as described previously.17 A For assessment of the efficiency of each method in identify- total of 1013 mouse genes were identified
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