Global human tissue profiling and protein network analysis reveals distinct levels of transcriptional germline-specificity and identifies target genes for male infertility
Global human tissue profiling and protein network analysis reveals distinct levels of transcriptional germline-specificity and identifies target genes for male infertility
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DOI：
10.1093/humrep/des301
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发表时间：
2012-11-01
影响因子：
6.1
通讯作者：
Primig, Michael
中科院分区：
文献类型：
--
作者：
Chalmel, Frederic;Lardenois, Aurelie;Primig, Michael
哺乳动物精子发生是一个涉及雄性性腺中体细胞和生殖细胞的复杂表达程序的过程。许多研究试图确定啮齿类和灵长类动物雄性减数分裂和配子发生的转录组。然而，很少有人类转录本与不同出生后发育阶段的睾丸体细胞和生殖细胞相关，并且与非睾丸组织相比，对它们的生殖系特异性水平知之甚少。我们使用基因芯片和总共47个诊断为隐睾的青春期前儿童的活检来量化人类转录本，不育的成年患者，其精子发生在连续的阶段被阻止，以及生育的对照个体。这些结果与来自富集的正常生殖细胞的数据、非睾丸表达数据、表型信息、预测的调控DNA结合基序和相互作用组数据相结合。在我们发现存在于人类睾丸中的体细胞和生殖细胞中的差异转录物浓度的3580个基因中，933个在45个胚胎和成人非睾丸组织中检测不到，包括许多在蛋白质水平上通过已发表的基因注释数据和组织学高通量蛋白质免疫检测试验证实的。使用基序富集分析，我们确定了调控启动子元件可能参与生殖系发育。最后，我们通过整合表达信号、相互作用组信息、表型和功能注释数据，构建了人类生育调控疾病网络，我们的结果为在细胞群体水平和整体体组织背景下研究出生后人类睾丸转录组提供了广泛的见解。此外，它们还为男性不育的遗传原因提供了线索，并将有助于鉴定新的癌症/睾丸基因作为癌症免疫疗法的靶点。
Mammalian spermatogenesis is a process that involves a complex expression program in both somatic and germ cells present in the male gonad. A number of studies have attempted to define the transcriptome of male meiosis and gametogenesis in rodents and primates. Few human transcripts, however, have been associated with testicular somatic cells and germ cells at different post-natal developmental stages and little is known about their level of germline-specificity compared with non-testicular tissues.We quantified human transcripts using GeneChips and a total of 47 biopsies from prepubertal children diagnosed with undescended testis, infertile adult patients whose spermatogenesis is arrested at consecutive stages and fertile control individuals. These results were integrated with data from enriched normal germ cells, non-testicular expression data, phenotype information, predicted regulatory DNA-binding motifs and interactome data.Among 3580 genes for which we found differential transcript concentrations in somatic and germ cells present in human testis, 933 were undetectable in 45 embryonic and adult non-testicular tissues, including many that were corroborated at protein level by published gene annotation data and histological high-throughput protein immunodetection assays. Using motif enrichment analyses, we identified regulatory promoter elements likely involved in germline development. Finally, we constructed a regulatory disease network for human fertility by integrating expression signals, interactome information, phenotypes and functional annotation data.Our results provide broad insight into the post-natal human testicular transcriptome at the level of cell populations and in a global somatic tissular context. Furthermore, they yield clues for genetic causes of male infertility and will facilitate the identification of novel cancer/testis genes as targets for cancer immunotherapies.