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• W2004117621 abstract "In the nematode Caenorhabditis elegans, formation of the long-lived dauer larva and adult aging are both controlled by insulin/insulin-like growth factor-1 signaling. Potentially, increased adult life span in daf-2 insulin/insulin-like growth factor-1 receptor mutants results from mis-expression in the adult of a dauer larva longevity program. By using oligonucleotide microarray analysis, we identified a dauer transcriptional signature in daf-2 mutant adults. By means of a nonbiased statistical approach, we identified gene classes whose expression is altered similarly in dauers and daf-2 mutants, which represent potential determinants of life span. These include known determinants of longevity; the small heat shock protein/α-crystallins are up-regulated in both milieus. The cytochrome P450, short-chain dehydrogenase/reductase, UDP-glucuronosyltransferase, and glutathione S-transferase (in daf-2 mutants) gene classes were also up-regulated. These four gene classes act together in metabolism and excretion of toxic endobiotic and xenobiotic metabolites. This suggests that diverse toxic lipophilic and electrophilic metabolites, disposed of by phase 1 and phase 2 drug metabolism, may be the major determinants of the molecular damage that causes aging. In addition, we observed down-regulation of genes linked to nutrient uptake, including nhx-2 and pep-2. These work together in the uptake of dipeptides in the intestine, implying dietary restriction in daf-2 mutants. Some gene groups up-regulated in dauers and/or daf-2 were enriched for certain promoter elements as follows: the daf-16-binding element, the heat shock-response element, the heat shock-associated sequence, or the hif-1-response element. By contrast, the daf-16-associated element was enriched in genes down-regulated in dauers and daf-2 mutants. Thus, particular promoter elements appear longevity-associated or aging associated. In the nematode Caenorhabditis elegans, formation of the long-lived dauer larva and adult aging are both controlled by insulin/insulin-like growth factor-1 signaling. Potentially, increased adult life span in daf-2 insulin/insulin-like growth factor-1 receptor mutants results from mis-expression in the adult of a dauer larva longevity program. By using oligonucleotide microarray analysis, we identified a dauer transcriptional signature in daf-2 mutant adults. By means of a nonbiased statistical approach, we identified gene classes whose expression is altered similarly in dauers and daf-2 mutants, which represent potential determinants of life span. These include known determinants of longevity; the small heat shock protein/α-crystallins are up-regulated in both milieus. The cytochrome P450, short-chain dehydrogenase/reductase, UDP-glucuronosyltransferase, and glutathione S-transferase (in daf-2 mutants) gene classes were also up-regulated. These four gene classes act together in metabolism and excretion of toxic endobiotic and xenobiotic metabolites. This suggests that diverse toxic lipophilic and electrophilic metabolites, disposed of by phase 1 and phase 2 drug metabolism, may be the major determinants of the molecular damage that causes aging. In addition, we observed down-regulation of genes linked to nutrient uptake, including nhx-2 and pep-2. These work together in the uptake of dipeptides in the intestine, implying dietary restriction in daf-2 mutants. Some gene groups up-regulated in dauers and/or daf-2 were enriched for certain promoter elements as follows: the daf-16-binding element, the heat shock-response element, the heat shock-associated sequence, or the hif-1-response element. By contrast, the daf-16-associated element was enriched in genes down-regulated in dauers and daf-2 mutants. Thus, particular promoter elements appear longevity-associated or aging associated. The biological processes that determine adult life span remain largely unknown. Over the last decade, analysis of mutants with altered rates of aging has led to the discovery of many genes and molecular pathways that act as determinants of life span. For example, the insulin/insulin-like growth factor 1 (IGF-1) 1The abbreviations used are: IGF-1, insulin-like growth factor 1; CYP, cytochrome P450; DBE, daf-16-binding element; DAE, daf-16-associated element; GST, glutathione S-transferase; HSE, heat shock element; HRE, hif-1-response element; HSAS, heat shock-associated site; IIS, insulin/IGF-1 signaling; L4, fourth stage larva; SDR, short-chain dehydrogenase/reductase; smHSP, small heat shock protein; TRP, transthyretin-related protein; UGT, UDP-glucuronosyltransferase; SOD, superoxide dismutase; PSSM, position specific score matrix; RBH, reciprocal best BLAST hit; RNAi, RNA interference; SAGE, serial analysis of gene expression; GO, gene ontology; Mt., topomountain. signaling system is a powerful regulator of aging in Caenorhabditis elegans: lowered insulin/IGF-1 signaling (IIS) can lead to more than a doubling of life span (the Age phenotype) (1Friedman D.B. Johnson T.E. Genetics. 1988; 118: 75-86Crossref PubMed Google Scholar, 2Kenyon C. Chang J. Gensch E. Rudener A. Tabtiang R. Nature. 1993; 366: 461-464Crossref PubMed Scopus (2523) Google Scholar, 3Kimura K.D. Tissenbaum H.A. Liu Y. Ruvkun G. Science. 1997; 277: 942-946Crossref PubMed Scopus (1742) Google Scholar). Similar effects have been observed in the fruit fly D. melanogaster (4Clancy D. Gems D. Harshman L.G. Oldham S. Hafen E. Leevers S.J. Partridge L. Science. 2001; 292: 104-106Crossref PubMed Scopus (1143) Google Scholar, 5Tatar M. Kopelman A. Epstein D. Tu M.-P. Yin C.-M. Garofalo R.S. Science. 2001; 292: 107-110Crossref PubMed Scopus (1267) Google Scholar). Recent findings suggest that life span in the mouse is influenced by both insulin and IGF-1 signaling (6Holzenberger M. Dupont J. Ducos B. Leneuve P. Geloen A. Even P. Cervera P. Le Bouc Y. Nature. 2003; 421: 182-187Crossref PubMed Scopus (1640) Google Scholar, 7Bluher M. Kahn B. Kahn C. Science. 2003; 299: 572-574Crossref PubMed Scopus (1071) Google Scholar). Thus, the role of IIS in the control of life span shows evolutionary conservation. However, the life span-determining processes that IIS regulates remain to be identified and are the topic of this report. The IIS system is one of several molecular signal transduction pathways that regulate larval diapause in C. elegans (8Riddle D.L. Albert P.S. Riddle D.L. Blumenthal T. Meyer B.J. Priess J.R. Caenorhabditis elegans II. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1997: 739-768Google Scholar). Under adverse environmental conditions (e.g. high temperature, low food, and high population density) developing larvae can form a long-lived, nonfeeding, and stress-resistant form: the dauer larva (9Cassada R.C. Russell R.L. Dev. Biol. 1975; 46: 326-342Crossref PubMed Scopus (624) Google Scholar). This diapausal form can survive for more than 3 months, during which time it can resume development if dauer-inducing conditions are reversed; by contrast, the adult C. elegans die of old age after only 2–3 weeks (10Klass M.R. Hirsh D.I. Nature. 1976; 260: 523-525Crossref PubMed Scopus (285) Google Scholar). Many mutations that reduce IIS result in constitutive dauer larva formation (the Daf-c phenotype), even under nondauer inducing conditions (8Riddle D.L. Albert P.S. Riddle D.L. Blumenthal T. Meyer B.J. Priess J.R. Caenorhabditis elegans II. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1997: 739-768Google Scholar). For example, mutations affecting the genes daf-2 (insulin/IGF-1 receptor) (3Kimura K.D. Tissenbaum H.A. Liu Y. Ruvkun G. Science. 1997; 277: 942-946Crossref PubMed Scopus (1742) Google Scholar) and age-1 (phosphatidylinositol 3-kinase) (11Morris J.Z. Tissenbaum H.A. Ruvkun G. Nature. 1996; 382: 536-538Crossref PubMed Scopus (706) Google Scholar) have this effect. Potentially, the large increase in life span seen in many IIS mutant adults reflects expression in the adult of dauer-associated longevity assurance processes (2Kenyon C. Chang J. Gensch E. Rudener A. Tabtiang R. Nature. 1993; 366: 461-464Crossref PubMed Scopus (2523) Google Scholar). A number of observations support this view; for example, dauer larvae and long-lived daf-2 and age-1 mutant adults have increased activity levels of the antioxidant enzyme superoxide dismutase (SOD) (12Anderson G.L. Can. J. Zool. 1982; 60: 288-291Crossref Google Scholar, 13Vanfleteren J.R. Biochem. J. 1993; 292: 605-608Crossref PubMed Scopus (333) Google Scholar, 14Vanfleteren J.R. De Vreese A. FASEB J. 1995; 9: 1355-1361Crossref PubMed Scopus (135) Google Scholar), and the mitochondrial Mn-SOD gene sod-3 shows increased mRNA levels in both dauer larvae and daf-2 mutants (15Honda Y. Honda S. FASEB J. 1999; 13: 1385-1393Crossref PubMed Scopus (599) Google Scholar, 16McElwee J. Bubb K. Thomas J. Aging Cell. 2003; 2: 111-121Crossref PubMed Scopus (336) Google Scholar, 17Murphy C.T. McCarroll S.A. Bargmann C.I. Fraser A. Kamath R.S. Ahringer J. Li H. Kenyon C.J. Nature. 2003; 424: 277-284Crossref PubMed Scopus (1711) Google Scholar). Additionally, severe daf-2 mutant adults exhibit a number of dauer-like behavioral characteristics, including cessation of feeding and adoption of an immobile, dauer-like posture (18Gems D. Sutton A.J. Sundermeyer M.L. Larson P.L. Albert P.S. King K.V. Edgley M. Riddle D.L. Genetics. 1998; 150: 129-155Crossref PubMed Google Scholar). Extensive information about gene expression patterns in dauer larvae and IIS mutant adults has been generated recently by transcriptional profile studies. Differences in mRNA abundance between dauer larvae and mixed stage growing populations have been measured by using serial analysis of gene expression (SAGE) (19Jones S. Riddle D. Pouzyrev A. Velculescu V. Hillier L. Eddy S. Stricklin S. Baillie D. Waterston R. Marra M. Genome Res. 2001; 11: 1346-1352Crossref PubMed Scopus (182) Google Scholar). More recently, microarray analysis was used to examine gene expression changes occurring during dauer exit and identified 1,984 genes showing significant expression changes (20Wang J. Kim S. Development (Camb.). 2003; 130: 1621-1634Crossref PubMed Scopus (231) Google Scholar). The increase in adult life span resulting from reduced IIS is suppressed by loss of function of the gene daf-16 (2Kenyon C. Chang J. Gensch E. Rudener A. Tabtiang R. Nature. 1993; 366: 461-464Crossref PubMed Scopus (2523) Google Scholar, 21Dorman J.B. Albinder B. Shroyer T. Kenyon C. Genetics. 1995; 141: 1399-1406Crossref PubMed Google Scholar, 22Larsen P.L. Albert P.S. Riddle D.L. Genetics. 1995; 139: 1567-1583Crossref PubMed Google Scholar). This gene encodes a FOXO class forkhead transcription factor (23 23Ogg S. Paradis S. Gottlieb S. Patterson G.I. Lee L. Tissenbaum H.A. Ruvkun G. Nature. 1997; 389: 994-999Crossref PubMed Scopus (1551) Google Scholar, 24Lin K. Dorman J.B. Rodan A. Kenyon C. Science. 1997; 278: 1319-1322Crossref PubMed Scopus (1214) Google Scholar), and it is therefore likely that the action of genes differentially regulated by DAF-16 is a major determinant of the effects of IIS on aging. Previously, several gene classes were identified that are regulated by IIS in a daf-16-dependent manner. For example, increases have been reported in age-1 and daf-2 mutants of enzyme activity or gene expression levels of antioxidant proteins such as catalase, Cu/Zn-SOD (cytosolic), and Mn-SOD (13Vanfleteren J.R. Biochem. J. 1993; 292: 605-608Crossref PubMed Scopus (333) Google Scholar, 15Honda Y. Honda S. FASEB J. 1999; 13: 1385-1393Crossref PubMed Scopus (599) Google Scholar, 25Larsen P.L. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8905-8909Crossref PubMed Scopus (596) Google Scholar). Also up-regulated are a number of heat shock proteins (26Walker G. White T. McColl G. Jenkins N. Babich S. Candido E. Johnson T. Lithgow G. J. Gerontol. A Biol. Sci. Med. Sci. 2001; 56: B281-B287Crossref PubMed Scopus (90) Google Scholar), and the heat shock transcription factor (hsf-1) is required for the Age phenotype (27Hsu A. Murphy C. Kenyon C. Science. 2003; 300: 1142-1145Crossref PubMed Scopus (1133) Google Scholar). Genome-wide surveys of transcriptional changes resulting from reduced IIS have been performed by using spotted DNA microarrays (16McElwee J. Bubb K. Thomas J. Aging Cell. 2003; 2: 111-121Crossref PubMed Scopus (336) Google Scholar, 17Murphy C.T. McCarroll S.A. Bargmann C.I. Fraser A. Kamath R.S. Ahringer J. Li H. Kenyon C.J. Nature. 2003; 424: 277-284Crossref PubMed Scopus (1711) Google Scholar). These have led to broad observations of correlations between genes regulated by IIS and particular functional processes or gene groups. An earlier comparison of data from over 500 microarray experiments identified a number of clusters of genes with correlated expression (28Kim S. Lund J. Kiraly M. Duke K. Jiang M. Stuart J. Eizinger A. Wylie B. Davidson G. Science. 2001; 293: 2087-2092Crossref PubMed Scopus (550) Google Scholar). These clusters were represented in the form of a three-dimensional topomap, in which co-expressed genes form “topomountains.” Reduced IIS increases expression of many genes associated with topomountain (Mt.) 15, and down-regulation of genes associated with Mts. 8, 19, 27, and 22 (16McElwee J. Bubb K. Thomas J. Aging Cell. 2003; 2: 111-121Crossref PubMed Scopus (336) Google Scholar). Moreover, reduced IIS leads to up-regulation of several functional gene classes (e.g. antibacterial peptides) and down-regulation of others (e.g. vitellogenins) (17Murphy C.T. McCarroll S.A. Bargmann C.I. Fraser A. Kamath R.S. Ahringer J. Li H. Kenyon C.J. Nature. 2003; 424: 277-284Crossref PubMed Scopus (1711) Google Scholar). Although insights have emerged from these studies, interpreting such transcriptional profiles remains difficult. Microarray experiments often generate lists of genes that are difficult to interpret in an unbiased fashion. Given a long enough list of differentially expressed genes, proof may be found for whatever theory is cherished by the investigator or fashionable in the research community. To circumvent this problem, we have taken a novel approach. We make the following assumptions. (a) Some common mechanisms increase life span in dauer larvae and daf-2 mutant adults. (b) These shared mechanisms are reflected by common changes in gene transcription. We have compared previously reported expression profiles of genes altered during dauer exit (20Wang J. Kim S. Development (Camb.). 2003; 130: 1621-1634Crossref PubMed Scopus (231) Google Scholar) with profiles for genes regulated by daf-2 in a daf-16-dependent manner, newly generated using whole genome oligonucleotide microarray analysis. We find that transcriptional changes occurring in dauer larvae are partially recapitulated in long-lived daf-2 adults. By using a nonbiased statistical analysis, we have identified a number of gene categories that are significantly enriched for members with altered expression in both dauer and daf-2 adult animals. This provides information about dauer-specific processes, which are mis-expressed in long-lived daf-2 mutant adults and potentially control longevity and aging. We also identify several promoter elements that are enriched among dauer- and daf-2-regulated genes. Strains and Media—The following strains were used for strain constructions: SS104 glp-4(bn2ts) I (29Beanan M. Strome S. Development (Camb.). 1992; 116: 755-766PubMed Google Scholar); DR1563 daf-2(e1370) III; DR1567 daf-2(m577) III (18Gems D. Sutton A.J. Sundermeyer M.L. Larson P.L. Albert P.S. King K.V. Edgley M. Riddle D.L. Genetics. 1998; 150: 129-155Crossref PubMed Google Scholar); and GR1307 daf-16(mgDf50) I (23 23Ogg S. Paradis S. Gottlieb S. Patterson G.I. Lee L. Tissenbaum H.A. Ruvkun G. Nature. 1997; 389: 994-999Crossref PubMed Scopus (1551) Google Scholar). From these, the following strains were constructed by standard means: glp-4 I; daf-2(m577) III, glp-4 daf-16; daf-2(m577), glp-4; daf-2(e1370), and glp-4 daf-16; daf-2(e1370). glp-4 is included in all strains to prevent egg and progeny production, thereby limiting mRNA analysis to that of somatic adult tissues. For routine strain maintenance, strain constructions, and life span analysis, nematodes were maintained on NGM agar plates, and Escherichia coli strain OP50 was used as a food source for all aspects of this study (30Sulston J. Hodgkin J. Wood W.B. The Nematode Caenorhabditis elegans. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1988: 587-606Google Scholar). For preparation of large numbers of nematodes for RNA isolation, 9-cm diameter enriched peptone NGM plates were used to maximize growth (31Lewis J. Fleming J. Epstein H. Shakes D. Caenorhabditis elegans: Modern Biological Analysis of an Organism. 48. Academic Press, San Diego1995: 4-29Google Scholar). Analysis of Life Span—For life span analysis, animals were raised at 15 °C and transferred to 25 °C at L4 stage. Life span of populations was measured on NGM plates as described previously (18Gems D. Sutton A.J. Sundermeyer M.L. Larson P.L. Albert P.S. King K.V. Edgley M. Riddle D.L. Genetics. 1998; 150: 129-155Crossref PubMed Google Scholar). Kaplan Meier analysis was conducted on survival data, and survival of populations of different genotypes were compared by using the nonparametric log rank test, using the statistical analysis package JMP 3.2.2 (SAS Institute Inc. Cary, NC). Isolation of RNA for Microarray Analysis—Nematodes were prepared for RNA extraction as follows. Eggs from each strain were first isolated from three large (9 cm) plates of just-starved, mixed-stage populations by alkaline hypochlorite treatment (30Sulston J. Hodgkin J. Wood W.B. The Nematode Caenorhabditis elegans. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1988: 587-606Google Scholar). These were allowed to hatch overnight in 50 ml of S media in 250-ml Erlenmeyer flasks at 20 °C with rotary shaking (200 rpm). The resulting synchronized L1 larvae were concentrated by centrifugation, pipetted onto eight large plates (subsequently pooled to give one biological replicate), and incubated at 15 °C. When most animals had reached L4 stage, plates were shifted up to 25 °C. This temperature shift at L4 served a dual purpose; it prevented dauer formation in the daf-16(+) strains (which are past the developmental point at which they can form dauers), and it ensured sterility in all strains (via glp-4). Worms were harvested for RNA extraction the following day (1-day-old sterile adults), by washing worms off plates with M9, followed by three additional washes with ice-cold M9 to remove residual bacteria. At the time of harvesting, cultures were sampled to check for the presence of dauer larvae, males, and carcasses, which might still remain from the hypochlorite treatment. Details of this and other aspects of this work are available at AgeBase (haldane.biol.ucl.ac.uk/publications.html). Whereas no dauer larvae were seen in daf-16(0) strains, a very small number were seen in one of the daf-16(+) samples. Small numbers of males and non-dauer larvae were observed in some samples to varying degrees; however, we did not observe any systematic contamination of particular sample genotypes. We did not observe any carcasses remaining from hypochlorite treatment in any samples. Finally, total RNA was isolated using TRIzol reagent (Invitrogen), followed by purification and concentration using RNEasy columns according to the manufacturer's instructions (Qiagen, www1.qiagen.com). The quality of RNA samples was confirmed on an Agilent Bioanalyzer 2100 (Agilent Technologies, www.chem.agilent.com). Oligonucleotide Microarray Analysis—Changes in transcript abundance was measured using C. elegans whole genome oligonucleotide microarrays (Affymetrix). We performed five biological replicates of each genotype. All Affymetrix protocols were performed at the University College London Institute of Child Health Gene Microarray Centre. The cRNA probe was generated by using standard Affymetrix protocols (www.affymetrix.com). Fragmented biotinylated probe was then hybridized to C. elegans whole genome arrays. Washing, labeling (streptavidin-phycoerythrin), and scanning followed standard procedures at the Institute of Child Health Gene Microarray Centre. Statistical Analysis—To calculate gene expression measures, the data sets were normalized as follows. Raw image files were converted to probe set data (.cel files) in Microarray Suite (MAS 5.0) (32.Deleted in proofGoogle Scholar) (www.stat.berkeley.edu/users/terry/zarray/Affy/GL_Workshop/genelogic2001.html). The 20 probe set data files were normalized together, and expression values were determined, using the Robust Multichip Average method (33Irizarry R. Hobbs B. Collin F. Beazer-Barclay Y. Antonellis K. Scherf U. Speed T. Biostatistics. 2003; 4: 249-264Crossref PubMed Scopus (8516) Google Scholar), implemented in the Affymetrix package (version 1.4.14) of the free statistical programming language R (www.r-project.org). Full array gene expression measures are available on the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo), accession numbers GSM28389–GSM28408. To identify differential gene expression between genotypes, we used significance analysis of microarrays, implemented in Microsoft Excel. A Δ value of 0.819 was chosen, which called 2,274 significant probe sets (1,348 up-regulated, 926 down-regulated), with a median false discovery rate of 5.06% (median number of falsely called probe sets = 116). To create the list of genes differentially regulated during dauer recovery, we re-analyzed the raw data from a previous study (20Wang J. Kim S. Development (Camb.). 2003; 130: 1621-1634Crossref PubMed Scopus (231) Google Scholar). Expression differences between time 0 and 12 h after dauer recovery were used to identify probes that were differentially expressed. Additionally, we calculated a new t test value for all gene changes, using a more stringent two-tailed Student's t test and assuming unequal variance. We then selected probes that showed at least a 2-fold (up or down) difference in expression and had a p value of <0.005. This resulted in a list of 2,535 differentially regulated genes (1,160 up-regulated, 1,375 down-regulated). To ensure the reliability of our data, we also performed several quality control procedures for both microarray formats. Briefly, we verified the accuracy of the microarray probes, and we identified probes that are predicted to hybridize to more than one gene (promiscuous probes) or to no gene (orphan probes). (For full analysis, see haldane.biol.ucl.ac.uk). Probes that could unambiguously be assigned to a single gene were used for EASE analysis (see below), whereas promiscuous probes were analyzed by hand for any potential functional significance. EASE Analysis—For our EASE analysis (see “Results” for explanation of the EASE application), we annotated every probe set on the C. elegans Affymetrix microarray and the Stanford cDNA microarray using information from a number of different data bases and data sets. We first associated each oligonucleotide probe set (or spotted array DNA probe) with its corresponding current curated gene entry. Next, the gene entry of each probe set was used to annotate the probe set or cDNA probe with functional information from Gene Ontology (GO) (34Ashburner M. Ball C.A. Blake J.A. Botstein D. Butler H. Cherry J.M. Davis A.P. Dolinski K.D.S. Eppig J.T. Harris M.A. Hill D.P. Issel-Tarver L. Kasarskis A. Lewis S. Matese J.C. Richardson J.E. Ringwald M. Rubin G.M. Sherlock G. Nat. Genet. 2000; 25: 25-29Crossref PubMed Scopus (27692) Google Scholar) (www.geneontology.org) and Interpro (35Mulder N. Apweiler R. Attwood T. Bairoch A. Barrell D. Bateman A. Binns D. Biswas M. Bradley P. Bork P. Bucher P. Copley R. Courcelle E. Das U. Durbin R. Falquet L. Fleischmann W. Griffiths-Jones S. Haft D. Harte N. Hulo N. Kahn D. Kanapin A. Krestyaninova M. Lopez R. Letunic I. Lonsdale D. Silventoinen V. Orchard S. Pagni M. Peyruc D. Ponting C. Selengut J. Servant F. Sigrist C. Vaughan R. Zdobnov E. Nucleic Acids Res. 2003; 31: 315-318Crossref PubMed Scopus (606) Google Scholar) (www.ebi.ac.uk/interpro). We also added functional information from several previous microarray and SAGE studies (16McElwee J. Bubb K. Thomas J. Aging Cell. 2003; 2: 111-121Crossref PubMed Scopus (336) Google Scholar, 17Murphy C.T. McCarroll S.A. Bargmann C.I. Fraser A. Kamath R.S. Ahringer J. Li H. Kenyon C.J. Nature. 2003; 424: 277-284Crossref PubMed Scopus (1711) Google Scholar, 19Jones S. Riddle D. Pouzyrev A. Velculescu V. Hillier L. Eddy S. Stricklin S. Baillie D. Waterston R. Marra M. Genome Res. 2001; 11: 1346-1352Crossref PubMed Scopus (182) Google Scholar, 20Wang J. Kim S. Development (Camb.). 2003; 130: 1621-1634Crossref PubMed Scopus (231) Google Scholar), as well as the yeast two-hybrid map of C. elegans (36Li S. Armstrong C.M. Bertin N. Ge H. Milstein S. Boxem M. Vidalain P.O. Han J.D. Chesneau A. Hao T. Goldberg D.S. Li N. Martinez M. Rual J.F. Lamesch P. Xu L. Tewari M. Wong S.L. Zhang L.V. Berriz G.F. Jacotot L. Vaglio P. Reboul J. Hirozane-Kishikawa T. Li Q. Gabel H.W. Elewa A. Baumgartner B. Rose D.J. Yu H. Bosak S. Sequerra R. Fraser A. Mango S.E. Saxton W.M. Strome S. Van Den Heuvel S. Piano F. Vandenhaute J. Sardet C. Gerstein M. Doucette-Stamm L. Gunsalus K.C. Harper J.W. Cusick M.E. Roth F.P. Hill D.E. Vidal M. Science. 2004; 303 (D. S.M. M.): 540-543Crossref PubMed Scopus (1453) Google Scholar). For a full description of source information and the files used in our complete EASE analysis, see haldane.biol.ucl.ac.uk. Analysis of Promoter Sequences—Genes with a given gene promoter motif in a defined region were identified using the program DNA Motif Searcher. This program uses a set of user-supplied DNA sequence motifs to search for additional motif instances in the genome of C. elegans. The set of motifs supplied by the user are interpreted into a position-specific score matrix (PSSM) that is used in the search step. By using this PSSM, the program can then identify the closest matching occurrences of the motif based on either a score cut-off, or it can identify the top X number of occurrences of the motif. For download or for a detailed explanation of how DNA Motif Searcher works, please see calliope.gs.washington.edu/papers/mcelwee2004a/software.html. For the analyses presented here, we identified the top 10,000 occurrences of each motif using local background nucleotide frequencies and then filtered the hits to identify genes that contained motif occurrences within 1,000 bp upstream of the translational start site and/or within intron 1. The PSSM for each search were derived from DBE (37Furuyama T. Nakazawa T. Nakano I. Mori N. Biochem. J. 2000; 349: 629-634Crossref PubMed Scopus (558) Google Scholar), DAE (17Murphy C.T. McCarroll S.A. Bargmann C.I. Fraser A. Kamath R.S. Ahringer J. Li H. Kenyon C.J. Nature. 2003; 424: 277-284Crossref PubMed Scopus (1711) Google Scholar), HSE, HSAS (38GuhaThakurta D. Palomar L. Stormo G. Tedesco P. Johnson T. Walker D. Lithgow G. Kim S. Link C. Genome Res. 2002; 12: 701-712Crossref PubMed Scopus (123) Google Scholar), and HRE. 2J. A. Powell-Coffman, personal communication. Analysis of Frequency of Drosophila Orthologues in Topomountains— Fly gene orthologues were identified by using an all-versus-all BLAST search for both worm and fly using a cut-off value of 1 × 10–8. These results from these searches were then used to identify reciprocal best BLAST hits using RBH Assigner (calliope.gs.washington.edu/papers/mcelwee2004a/software.html). The resulting list of RBHs were used for this analysis, using a score cut-off of 100.0 or greater (2,623 of 3,609 RBHs). By using this list of RBHs, the fly orthologues were placed into orthologous mountains. The total number of C. elegans genes in each mountain was calculated, and the percent representation was determined as the fraction of fly genes found in the orthologous mountain. Genes that are transcriptionally regulated by the DAF-16 transcription factor must include some that are direct determinants of life span. DAF-16-regulated genes have been identified by using DNA microarray analysis (spotted arrays) (16McElwee J. Bubb K. Thomas J. Aging Cell. 2003; 2: 111-121Crossref PubMed Scopus (336) Google Scholar, 17Murphy C.T. McCarroll S.A. Bargmann C.I. Fraser A. Kamath R.S. Ahringer J. Li H. Kenyon C.J. Nature. 2003; 424: 277-284Crossref PubMed Scopus (1711) Google Scholar). Here we have taken the approach of comparing lists of genes whose expression is altered in daf-2 mutants and in dauer larvae, performing a nonbiased search for classes of genes that are enriched in both cases. To this end we prepared a new list of daf-16-regulated genes, using whole genome oligonucleotide (Affymetrix) arrays. The dauer-regulated gene list was derived from a previous study (20Wang J. Kim S. Development (Camb.). 2003; 130: 1621-1634Crossref PubMed Scopus (231) Google Scholar). daf-2 mutants are all long-lived but show variable degrees of pleiotropy (18Gems D. Sutton A.J. Sundermeyer M.L. Larson P.L. Albert P.S. King K.V. Edgley M. Riddle D.L. Genetics. 1998; 150: 129-155Crossref PubMed Google Scholar). To reduce the probability of identifying allele-specific targets unlinked to aging, we used two daf-2 alleles for the microarray analysis: daf-2(m577) (class 1) and daf-2(e1370) (class 2, more pleiotropic). We studied age-synchronized 1-dayold adults, in which reproduction was blocked using the glp-4(bn2ts) mutation (29Beanan M. Strome S. Development (Camb.). 1992; 116: 755-766PubMed Google Scholar). This temperature-sensitive mutation blocks mitotic proliferation of the germ line at 25 °C but is fertile at 15 °C. Nematodes were shifted from 15 to 25 °C at the L4 stage. In C. elegans, an increase in life span results from removal of the germ line, whether" @default.
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