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The Conserved Transcriptome in Human and Rodent Male Gametogenesis

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The conserved transcriptome in human and rodent male gametogenesis Fre´ de´ ric Chalmel*, Antoine D. Rolland†, Christa Niederhauser-Wiederkehr*, Sanny S. W. Chung‡, Philippe Demougin*, Alexandre Gattiker*, James Moore*, Jean-Jacques Patard§, Debra J. Wolgemuth‡, Bernard Je´ gou†, and Michael Primig*¶ʈ *Biozentrum and Swiss Institute of Bioinformatics, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland; †Institut National de la Sante´et de la Recherche Me´dicale U625, Group d’Etude de la Reproduction chez l’Homme et les Mammife`res, Institut Fe´de´ ratif de Recherche 140; Universite´de Rennes I, Campus de Beaulieu , F-35042 Rennes, France; ‡Columbia University Medical Center, Black Building 1613, 630 West 168th Street, New York, NY 10032; and §Centre Hospitalier Universitaire Re´gional Pontchaillou, Service d’Urologie, F-35000 Rennes, France Communicated by Ronald W. Davis, Stanford University School of Medicine, Palo Alto, CA, March 15, 2007 (received for review October 12, 2006) We report a cross-species expression profiling analysis of the Gene Ontology Consortium (20), shows that genes known or human, mouse, and rat male meiotic transcriptional program, using predicted to be important for meiosis and reproduction are enriched germ cell populations, whole gonads, and high-density significantly enriched among loci expressed in testicular cell oligonucleotide microarrays (GeneChips). Among 35% of the types (13). Thus, profiling experiments likely help identify protein-coding genes present in rodent and human genomes that factors important for the meiotic developmental pathway in both were found to be differentially expressed between germ cells and yeast (3, 4) and mammals (14). somatic controls, a key group of 357 conserved core loci was In this study, enriched mitotic, meiotic, and postmeiotic germ identified that displays highly similar meiotic and postmeiotic cells were compared with somatic Sertoli cells to select differ- patterns of transcriptional induction across all three species. Genes entially expressed mouse and rat loci. Among them, a group of known to be important for sexual reproduction are significantly conserved core genes were identified whose expression profiles enriched among differentially expressed core loci and a smaller in meiotic and postmeiotic germ cells are highly similar between group of conserved genes not detected in 17 nontesticular somatic rodents and human. Numerous potentially testis-specific loci tissues, correlating transcriptional activation and essential func- were found by comparing the transcriptional activity of differ- tion in the male germ line. Some genes implicated in the etiology entially expressed genes in testis to 17 somatic control tissues. of cancer are found to be strongly transcribed in testis, suggesting Using whole-genome arrays covering all currently annotated that these genes may play unexpected roles in sexual reproduc- genes in rodent and human genomes together with a compre- tion. Expression profiling data further identified numerous con- hensive cross-species experimental approach revealed several served genes of biological and clinical interest previously unasso- hundred novel genes likely to be involved in the mammalian ciated with the mammalian male germ line. meiotic process. A graphical display of the expression data is available from the GermOnline database (www.germonline.org) bioinformatics ͉ spermatogenesis ͉ transcriptome that can be searched for individual genes as well as groups of loci (21). Additional information, including analysis software and eiosis and gametogenesis are critical processes in the raw data, is available from the authors upon request [see Mtransmission of genetic material to subsequent genera- supporting information (SI) Results]. tions during sexual reproduction. A large number of genes Results and Discussion involved in this process have been characterized in model organisms, such as budding and fission yeast (1–4) and nema- Defining the Mammalian Testicular Expression Program. mRNA todes (5), but comparatively few essential and specifically ex- from highly enriched populations of rodent somatic Sertoli cells pressed loci are known in mammals, particularly humans (6, 7). and mitotic spermatogonia, meiotic spermatocytes and postmei- In males, mitotically growing spermatogonia develop into mei- otic round spermatids as well as isolated seminiferous tubules otic spermatocytes that give rise to haploid spermatids which and total testis samples were analyzed by using high density differentiate into mature sperm. This pathway is controlled in oligonucleotide microarrays [Fig. 1; see also SI Table 1]. Total and cRNA quality was found to be very homogenous (SI Fig. 5 part by somatic Sertoli cells that physically interact with germ a and b) and the overall reproducibility of the data was excellent cells and communicate with them by hormonal cues (for review, as shown by a distance matrix (SI Fig. 5c). The transcripts see refs. 8–11). Many of the loci required for meiotic landmark events such as recombination and gamete formation are known to be expressed only in cells capable of undergoing the process, Author contributions: F.C., A.D.R., C.N.-W., B.J., and M.P. contributed equally to this work; but the regulatory network that confers germ-line-specific tran- A.D.R., S.S.W.C., D.J.W., B.J., and M.P. designed research; A.D.R., S.S.W.C., P.D., A.G., and scription in higher eukaryotes is poorly understood, especially at J.-J.P. performed research; F.C., A.D.R., A.G., J.-J.P., D.J.W., and B.J. contributed new the mitotic and meiotic stages (12). reagents/analytic tools; F.C., A.D.R., C.N.-W., S.S.W.C., J.M., and M.P. analyzed data; and M.P. wrote the paper. Recent studies have identified a large number of genes active during gametogenesis using testicular expressed sequence tag The authors declare no conflict of interest. libraries, serial analysis of gene expression (SAGE) and microar- Freely available online through the PNAS open access option. ray profiling of enriched germ cell and testis samples from Abbreviation: GO, gene ontology. rodents (13, 14). These array studies covered approximately one ¶Present address: Institut National de la Sante´et de la Recherche Me´dicale U 625, Institut Fe´de´ ratif de Recherche 140; Universite´de Rennes I, Avenue du Ge´ne´ ral Leclerc, F-35042 third of the genes currently known to be encoded by the mouse Rennes, France. and rat genomes and showed that differentiating germ cells ʈTo whom correspondence should be addressed. E-mail: [email protected]. up-regulate hundreds of transcripts (15–17), including many that Data deposition: The data reported in this paper have been deposited in the European encode germ-line-specific products (18). Although numerous Bioinformatics Institute (EBI) ArrayExpress database, www.ebi.ac.uk/arrayexpress mRNAs have also been detected in mature human sperm, (accession no. E-TABM-130). regulation of gene expression underlying germ cell development This article contains supporting information online at www.pnas.org/cgi/content/full/ and the roles these transcripts may play during embryogenesis 0701883104/DC1. remain unclear (19). Statistical analysis, using data from the © 2007 by The National Academy of Sciences of the USA 8346–8351 ͉ PNAS ͉ May 15, 2007 ͉ vol. 104 ͉ no. 20 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0701883104 Downloaded by guest on September 29, 2021 Fig. 1. Schematic representation of the mammalian testis. (a) Drawing of the testis containing seminiferous tubules and the epididymis. (b) Sertoli nurse cell associated with a mitotic spermatogonium, a meiotic pachytene spermato- cyte, and round and elongated postmeiotic spermatids. corresponding to GeneChip probe set IDs were annotated by using information provided by the GeneChip manufacturer and additional data retrieved by links to external databases (SI Fig. 6 a and b). Genes whose expression signals varied significantly between Sertoli cells, germ cells, tubules, and whole-organ controls were designated as ‘‘differentially expressed in testis’’ (DET) (this ab- breviation is also used in the BioMart query form of GermOnline). This approach identified 9,280 and 5,895 probe sets that map to 7,066 and 5,140 unique protein-coding mouse and rat genes, respectively, representing Ϸ36% of the transcripts detected by the rodent GeneChips (22, 23). The differentially expressed probe sets were further classified by using a hierarchical clustering algorithm (SI Fig. 7 a and b). Somatic Sertoli cells and mitotic spermatogonia show similar profiles, distinguishing them from meiotic spermato- Fig. 2. The core testicular transcriptome in mammals (CDET). (a) Venn diagram of conserved probesets (top number) and corresponding genes (bot- cytes and postmeiotic spermatids clustered together with tubules tom number) represented on each GeneChip. (b) Summarizes the filtration and total testis samples (top dendrogram). This finding is in and clustering procedure. (c) Heatmaps of expression patterns in four clusters agreement with earlier observations using similar rat samples (15). for three species as indicated. Numbers of probe sets and corresponding genes Subsequently, human chondrocytes and smooth vascular muscle in each expression cluster are shown at the left. Sample names are Sertoli cells cells were compared with enriched pachytene spermatocytes and (SE), spermatogonia (SG), spermatocytes (SC), spermatids (ST), tubules (TU), postmeiotic round spermatids, yielding 6,499 probe sets that cor- and total testis (TT). Human
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  • Frequent Loss of Heterozygosity Targeting the Inactive X Chromosome in Melanoma

    Frequent Loss of Heterozygosity Targeting the Inactive X Chromosome in Melanoma

    6476 Vol. 9, 6476–6482, December 15, 2003 Clinical Cancer Research Frequent Loss of Heterozygosity Targeting the Inactive X Chromosome in Melanoma James O. Indsto,1 Najah T. Nassif,2 INTRODUCTION Richard F. Kefford,1 and Graham J. Mann1 Chromosomal deletions and amplification events are fre- 1Westmead Institute for Cancer Research, University of Sydney at quent in advanced neoplasms and provide evidence for the Westmead Millennium Institute, Westmead, New South Wales, existence and location of putative tumor suppressor genes Australia, and 2Department of Cell and Molecular Biology, University (TSGs) and oncogenes. In melanoma, 9p and 10q deletions are of Technology, Sydney, New South Wales, Australia most frequent, and losses on 6q, 11q, 1p, 15p, 17q, and 18q are also frequently found (1, 2). However, no studies have focused on the X chromosome. In the human female, random inactiva- ABSTRACT tion of one copy of an X chromosome by hypermethylation is an After previous preliminary observations of paradoxical early event in embryogenesis, resulting in most tissues being a deletion events affecting the inactive X chromosome in mel- mosaic in terms of X inactivation status. Neoplasms, being anoma, we have surveyed the X chromosome for deletions clonal expansions of single precursor cells, usually share a using 23 polymorphic microsatellite markers in 28 inform- common X inactivation status. This can be conveniently assayed ative (female XX) metastatic melanomas. Ten tumors (36%) using the methylation-sensitive restriction enzyme HpaII, which showed at least one loss of heterozygosity (LOH) event, and has a recognition site within the highly polymorphic exon 1 in two cases an entire chromosome showed LOH at all CAG repeat (ARTR) in the androgen receptor (AR) gene.