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Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas

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GENOME BIOLOGY 2008年第10期9卷 R150-R150页

作者： Westermann, Frank Muth, Daniel Benner, Axel Bauer, Tobias Henrich, Kai-Oliver Oberthuer, Andre Brors, Benedikt Beissbarth, Tim Vandesompele, Jo Pattyn, Filip Hero, Barbara Koenig, Rainer Fischer, Matthias Schwab, Manfred German Canc Res Ctr Dept Tumor Genet D-69120 Heidelberg Germany German Canc Res Ctr Dept Biostat D-69120 Heidelberg Germany Univ Childrens Hosp Cologne Dept Pediat Oncol D-50924 Cologne Germany German Canc Res Ctr Div Mol Genome Anal D-69120 Heidelberg Germany Univ Ghent Ctr Med Genet B-9000 Ghent Belgium

Background Amplified MYCN oncogene resulting in deregulated MYCN transcriptional activity is observed in 20% of neuroblastomas and identifies a highly aggressive subtype. In MYCN single-copy neuroblastomas, elevated MYCN mRNA and protein levels are paradoxically associated with a more favorable clinical phenotype, including disseminated tumors that subsequently regress spontaneously (stage 4s-non-amplified). In this study, we asked whether distinct transcriptional MYCN or c-MYC activities are associated with specific neuroblastoma phenotypes. Results We defined a core set of direct MYCN/c-MYC target genes by applying gene expression profiling and Chromatin Immunoprecipitation (ChIP, ChIP-chip) in neuroblastoma cells that allow conditional regulation of MYCN and c-MY C. Their transcript levels were analyzed in 251 primary neuroblastomas. Compared to localized-non-amplified neuroblastomas, MYCN/c-MYC target gene expression gradually increases from stage 4s-non-amplified through stage 4-non-amplified to MYCN amplified tumors. This was associated with MYCN activation in stage 4s-non-amplified and predominantly c-MYC activation in stage 4-nonamplified tumors. A defined set of MYCN/c-MYC target genes was induced in stage 4-nonamplified but not in stage 4s-non-amplified. In line with this, high expression of a subset of MYCN/c-MYC target genes identifies a patient subtype with poor overall survival independent of the established risk markers amplified MYCN, disease stage, and age at diagnosis. Conclusions High MYCN/c-MYC target gene expression is a hallmark of malignant neuroblastoma progression that is predominantly driven by c- MYC in stage 4-non-amplified tumors. In contrast, moderate MYCN function gain in stage 4s-non-amplified tumors induces only a restricted set of target genes that is still compatible with spontaneous regression.

关键词： Neuroblastoma additional data file Neuroblastoma Cell Line Target Gene Promoter MYCN Expression

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Encapsulated in silica: genome, proteome and physiology of the thermophilic bacterium Anoxybacillus flavithermus WK1

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GENOME BIOLOGY 2008年第11期9卷 R161-R161页

作者： Saw, Jimmy H. Mountain, Bruce W. Feng, Lu Omelchenko, Marina V. Hou, Shaobin Saito, Jennifer A. Stott, Matthew B. Li, Dan Zhao, Guang Wu, Junli Galperin, Michael Y. Koonin, Eugene V. Makarova, Kira S. Wolf, Yuri I. Rigden, Daniel J. Dunfield, Peter F. Wang, Lei Alam, Maqsudul Nankai Univ TEDA Sch Biol Sci & Biotechnol Tianjin 300457 Peoples R China Univ Hawaii Dept Microbiol Honolulu HI 96822 USA GNS Sci Extremophile Res Grp Taupo 3352 New Zealand Tianjin Res Ctr Funct Genom & Biochip Tianjin 300457 Peoples R China Minist Educ Key Lab Mol Microbiol & Technol Tianjin 300457 Peoples R China NIH Natl Ctr Biotechnol Informat Natl Lib Med Bethesda MD 20894 USA Univ Hawaii Coll Nat Sci Honolulu HI 96822 USA Univ Liverpool Sch Biol Sci Liverpool L69 7ZB Merseyside England Univ Calgary Dept Biol Sci Calgary AB T2N 1N4 Canada

Background Gram-positive bacteria of the genus Anoxybacillus have been found in diverse thermophilic habitats such as geothermal hot springs, manure, and in processed foods such as gelatin and milk powder. Anoxybacillus flavithermus is a facultatively anaerobic bacterium found in supersaturated silica solutions and in opaline silica sinter. The ability of A. flavithermus to grow in super-saturated silica solutions makes it an ideal subject to study the processes of sinter formation, which might be similar to the biomineralization processes that occurred at the dawn of life. Results We report here the complete genome sequence of Anoxybacillus flavithermus strain WK1, isolated from the waste water drain at the Wairakei geothermal power station in New Zealand. It consists of a single chromosome of 2,846,746 base pairs and is predicted to encode 2,863 proteins. In silico genome analysis identified several enzymes that could be involved in silica adaptation and biofilm formation, and their predicted functions were experimentally validated in vitro. Proteomic analysis confirmed the regulation of biofilm-related proteins and crucial enzymes for the synthesis of long-chainpolyamines as constituents of silica nanospheres. Conclusions Microbial fossils preserved in silica and silica sinters are excellent objects for studying ancient life, a new paleobiological frontier. An integrated analysis of the A. flavithermus genome and proteome provides the first glimpse of metabolic adaptation during silicification and sinter formation. Comparative genome analysis suggests an extensive gene loss in the Anoxybacillus/Geobacillus branch after its divergence from other bacilli.

关键词： Putrescine additional data file Arginase Cluster Regularly Interspaced Short Palindromic Repeat Arginine Decarboxylase

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Systematic analysis of transcribed loci in ENCODE regions using RACE sequencing reveals extensive transcription in the human genome

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GENOME BIOLOGY 2008年第1期9卷 R3-R3页

作者： QianWu, Jia Du, Jiang Rozowsky, Joel Zhang, Zhengdong Urban, Alexander E. Euskirchen, Ghia Weissman, Sherman Gerstein, Mark Snyder, Michael Yale Univ Mol Cellular & Dev Biol Dept New Haven CT 06511 USA Yale Univ Dept Comp Sci New Haven CT 06511 USA Yale Univ Dept Biochem & Mol Biophys New Haven CT 06511 USA Yale Univ Dept Genet New Haven CT 06511 USA

Background: Recent studies of the mammalian transcriptome have revealed a large number of additional transcribed regions and extraordinary complexity in transcript diversity. However, there is still much uncertainty regarding precisely what portion of the genome is transcribed, the exact structures of these novel transcripts, and the levels of the transcripts produced. Results: We have interrogated the transcribed loci in 420 selected ENCyclopedia Of DNA Elements (ENCODE) regions using rapid amplification of cDNA ends (RACE) sequencing. We analyzed annotated known gene regions, but primarily we focused on novel transcriptionally active regions (TARs), which were previously identified by high-density oligonucleotide tiling arrays and on random regions that were not believed to be transcribed. We found RACE sequencing to be very sensitive and were able to detect low levels of transcripts in specific cell types that were not detectable by microarrays. We also observed many instances of sense-antisense transcripts;further analysis suggests that many of the antisense transcripts (but not all) may be artifacts generated from the reverse transcription reaction. Our results show that the majority of the novel TARs analyzed (60%) are connected to other novel TARs or known exons. Of previously unannotated random regions, 17% were shown to produce overlapping transcripts. Furthermore, it is estimated that 9% of the novel transcripts encode proteins. Conclusion: We conclude that RACE sequencing is an efficient, sensitive, and highly accurate method for characterization of the transcriptome of specific cell/tissue types. Using this method, it appears that much of the genome is represented in polyA+ RNA. Moreover, a fraction of the novel RNAs can encode protein and are likely to be functional.

关键词： additional data file Antisense Transcript Tiling Array Antisense Transcription Encode Region

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Whole genome transcriptome polymorphisms in Arabidopsis thaliana

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GENOME BIOLOGY 2008年第11期9卷 R165-R165页

作者： Zhang, Xu Byrnes, Jake K. Gal, Thomas S. Li, Wen-Hsiung Borevitz, Justin O. Univ Chicago Dept Ecol & Evolut Chicago IL 60637 USA

Whole genome tiling arrays are a key tool for profiling global genetic and expression variation. In this study we present our methods for detecting transcript level variation, splicing variation and allele specific expression in Arabidopsis thaliana. We also developed a generalized Hidden Markov Model for profiling transcribed fragment variation de novo. Our study demonstrates that whole genome tiling arrays are a powerful platform for dissecting natural transcriptome variation at multi-dimension and high resolution.

关键词： additional data file Probe Intensity Allele Specific Expression Differential Splice Differential Segment

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Systems biology-defined NF-κB regulons, interacting signal pathways and networks are implicated in the malignant phenotype of head and neck cancer cell lines differing in p53 status

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GENOME BIOLOGY 2008年第3期9卷 R53-R53页

作者： Yan, Bin Chen, Guang Saigal, Kunal Yang, Xinping Jensen, Shane T. Van Waes, Carter Stoeckert, Christian J. Chen, Zhong NIDCD Head & Neck Surg Branch NIH Bethesda MD 20892 USA Univ Penn Dept Bioengn Philadelphia PA 19104 USA Univ Penn Ctr Bioinformat Philadelphia PA 19104 USA Univ Penn NIH Pfizer Clin Res Training Program Award Philadelphia PA 19104 USA Univ Penn Wharton Sch Dept Stat Philadelphia PA 19104 USA Univ Penn Sch Med Dept Genet Philadelphia PA 19104 USA

Background: Aberrant activation of the nuclear factor kappaB (NF-kappa B) pathway has been previously implicated as a crucial signal promoting tumorigenesis. However, how NF-kappa B acts as a key regulatory node to modulate global gene expression, and contributes to the malignant heterogeneity of head and neck cancer, is not well understood. Results: To address this question, we used a newly developed computational strategy, COGRIM (Clustering Of Gene Regulons using Integrated Modeling), to identify NF-kappa B regulons (a set of genes under regulation of the same transcription factor) for 1,265 genes differentially expressed by head and neck cancer cell lines differing in p53 status. There were 748 NF-kappa B targets predicted and individually annotated for RELA, NF-kappa BI or cREL regulation, and a prevalence of RELA related genes was observed in over-expressed clusters in a tumor subset. Using Ingenuity Pathway Analysis, the NF-kappa B targets were reverse-engineered into annotated signature networks and pathways, revealing relationships broadly altered in cancer lines (activated proinflammatory and down-regulated Wnt/beta-catenin and transforming growthfactor-beta pathways), or specifically defective in cancer subsets (growth factors, cytokines, integrins, receptors and intermediate kinases). Representatives of predicted NF-kappa B target genes were experimentally validated through modulation by tumor necrosis factor-alpha or small interfering RNA for RELA or NF-kappa BI. Conclusion: NF-kappa B globally regulates diverse gene programs that are organized in signal networks and pathways differing in cancer subsets with distinct p53 status. The concerted alterations in gene expression patterns reflect cross-talk among NF-kappa B and other pathways, which may provide a basis for molecular classifications and targeted therapeutics for heterogeneous subsets of head and neck or other cancers.

关键词： additional data file Ingenuity Pathway Analysis Human Normal Keratinocytes Inositol Phosphate Metabolism Markov Chain Monte Carlo Implementation

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Evolutionary-new centromeres preferentially emerge within gene deserts

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GENOME BIOLOGY 2008年第12期9卷 R173-R173页

作者： Lomiento, Mariana Jiang, Zhaoshi D'Addabbo, Pietro Eichler, Evan E. Rocchi, Mariano Univ Bari Dept Genet & Microbiol I-70126 Bari Italy Univ Washington Sch Med Dept Genome Sci Seattle WA 98195 USA Univ Washington Howard Hughes Med Inst Seattle WA 98195 USA

Background: Evolutionary-new centromeres (ENCs) result from the seeding of a centromere at an ectopic location along the chromosome during evolution. The novel centromere rapidly acquires the complex structure typical of eukaryote centromeres. This phenomenon has played an important role in shaping primate karyotypes. A recent study on the evolutionary-new centromere of macaque chromosome 4 (human 6) showed that the evolutionary-new centromere domain was deeply restructured, following the seeding, with respect to the corresponding human region assumed as ancestral. It was also demonstrated that the region was devoid of genes. We hypothesized that these two observations were not merely coincidental and that the absence of genes in the seeding area constituted a crucial condition for the evolutionary-new centromere fixation in the population. Results: To test our hypothesis, we characterized 14 evolutionary-new centromeres selected according to conservative criteria. Using different experimental approaches, we assessed the extent of genomic restructuring. We then determined the gene density in the ancestral domain where each evolutionary-new centromere was seeded. \Conclusions: Our study suggests that restructuring of the seeding regions is an intrinsic property of novel evolutionary centromeres that could be regarded as potentially detrimental to the normal functioning of genes embedded in the region. The absence of genes, which was found to be of high statistical significance, appeared as a unique favorable scenario permissive of evolutionary-new centromere fixation in the population.

关键词： Bacterial Artificial Chromosome additional data file Bacterial Artificial Chromosome Clone Segmental Duplication Bacterial Artificial Chromosome Library

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Comparative analysis reveals signatures of differentiation amid genomic polymorphism in Lake Malawi cichlids

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GENOME BIOLOGY 2008年第7期9卷 R113-R113页

作者： Loh, Yong-Hwee E. Katz, Lee S. Mims, Meryl C. Kocher, Thomas D. Yi, Soojin V. Streelman, J. Todd Georgia Inst Technol Petit Inst Bioengn & Biosci Sch Biol Atlanta GA 30332 USA Univ Maryland Dept Biol College Pk MD 20742 USA

Background: Cichlid fish from East Africa are remarkable for phenotypic and behavioral diversity on a backdrop of genomic similarity. In 2006, the Joint Genome Institute completed low coverage survey sequencing of the genomes of five phenotypically and ecologically diverse Lake Malawi species. We report a computational and comparative analysis of these data that provides insight into the mechanisms that make closely related species different from one another. Results: We produced assemblies for the five species ranging in aggregate length from 68 to 79 megabase pairs, identified putative orthologs for more than 12,000 human genes, and predicted more than 32,000 cross-species single nucleotide polymorphisms (SNPs). Nucleotide diversity was lower than that found among laboratory strains of the zebrafish. We collected around 36,000 genotypes to validate a subset of SNPs within and among populations and across multiple individuals of about 75 Lake Malawi species. Notably, there were no fixed differences observed between focal species nor between major lineages. Roughly 3% to 5% of loci surveyed are statistical outliers for genetic differentiation (F-ST) within species, between species, and between major lineages. Outliers for FST are candidate genes that may have experienced a history of natural selection in the Malawi lineage. Conclusion: We present a novel genome sequencing strategy, which is useful when evolutionary diversity is the question of interest. Lake Malawi cichlids are phenotypically and behaviorally diverse, but they appear genetically like a subdivided population. The unique structure of Lake Malawl cichlid genomes should facilitate conceptually new experiments, employing SNPs to identity genotype-phenotype association, using the entire species flock as a mapping panel.

关键词： additional data file Genetic Cluster Joint Genome Institute Cichlid Species Species Flock

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Diarrhea as a cause of mortality in a mouse model of infectious colitis

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GENOME BIOLOGY 2008年第8期9卷 R122-R122页

作者： Borenshtein, Diana Fry, Rebecca C. Groff, Elizabeth B. Nambiar, Prashant R. Carey, Vincent J. Fox, James G. Schauer, David B. MIT Dept Biol Engn Cambridge MA 02139 USA MIT Ctr Environm Hlth Sci Cambridge MA 02139 USA MIT Div Comparat Med Cambridge MA 02139 USA Harvard Univ Sch Med Boston MA 02115 USA

Background: Comparative characterization of genome-wide transcriptional changes during infection can help elucidate the mechanisms underlying host susceptibility. In this study, transcriptional profiling of the mouse colon was carried out in two cognate lines of mice that differ in their response to Citrobacter rodentium infection;susceptible inbred FVBN and resistant outbred Swiss Webster mice. Gene expression in the distal colon was determined prior to infection, and at four and nine days post-inoculation using a whole mouse genome Affymetrix array. Results: Computational analysis identified 462 probe sets more than 2-fold differentially expressed between uninoculated resistant and susceptible mice. In response to C. rodentium infection, 5,123 probe sets were differentially expressed in one or both lines of mice. Microarray data were validated by quantitative real-time RT-PCR for 35 selected genes and were found to have a 94% concordance rate. Transcripts represented by 1,547 probe sets were differentially expressed between susceptible and resistant mice regardless of infection status, a host effect. Genes associated with transport were over-represented to a greater extent than even immune responserelated genes. Electrolyte analysis revealed reduction in serum levels of chloride and sodium in susceptible animals. Conclusion: The results support the hypothesis that mortality in C. rodentium-infected susceptible mice is associated with impaired intestinal ion transport and development of fatal fluid loss and dehydration. These studies contribute to our understanding of the pathogenesis of C. rodentium and suggest novel strategies for the prevention and treatment of diarrhea associated with intestinal bacterial infections.

关键词： Gene Ontology Cystic Fibrosis Transmembrane Conductance Regulator additional data file Distal Colon Uninoculated Control

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Translational control plays a prominent role in the hepatocytic differentiation of HepaRG liver progenitor cells

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GENOME BIOLOGY 2008年第1期9卷 R19-R19页

作者： Parent, Romain Beretta, Laura Fred Hutchinson Canc Res Ctr Div Publ Hlth Sci Seattle WA 98109 USA

Background: We investigated the molecular events associated with the differentiation of liver progenitor cells into functional and polarized hepatocytes, using human HepaRG cells that display potent hepatocytic differentiation-inducible properties and share some features with liver progenitor cells. Results: Profiling of total and of polysome-bound transcripts isolated from HepaRG cells undergoing hepatocytic differentiation was performed. A group of 3,071 probe sets was reproducibly regulated by at least 2-fold in total or in polysome-bound RNA populations, upon differentiation. The fold changes in the total and the polysome-bound RNA populations for these 3,071 probe sets were poorly correlated (R=0.38). Moreover, while the majority of the regulated polysome-bound RNA probe sets were up-regulated upon differentiation, the majority of the regulated probe sets selected from the total RNA population was down-regulated. Genes translationally up-regulated were associated with cell cycle inhibition, increased susceptibility to apoptosis and innate immunity. In contrast, genes transcriptionally up-regulated during differentiation corresponded in the majority to liver-enriched transcripts involved in lipid homeostasis and drug metabolism. Finally, several epithelial and hepato-specific transcripts were strongly induced in the total RNA population but were translationally repressed. Conclusion: Translational regulation is the main genomic event associated with hepatocytic differentiation of liver progenitor cells in vitro and targets genes critical for moderating hepatocellular growth, cell death and susceptibility to pathogens. Transcriptional regulation targets specifically liver-enriched transcripts vital for establishing normal hepatic energy homeostasis, cell morphology and polarization. The hepatocytic differentiation is also accompanied by a reduction of the transcript content complexity.

关键词： additional data file Translational Control Peroxisome Proliferative Activate Receptor Alpha HepaRG Cell Liver Progenitor Cell

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Deoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide

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BREAST CANCER RESEARCH 2008年第6期10卷 1-16页

作者： Krishnamurthy, Kannan Wang, Guanghu Rokhfeld, Dmitriy Bieberich, Erhard Med Coll Georgia Sch Med Inst Mol Med & Genet Augusta GA 30912 USA Med Coll Georgia Sch Grad Studies Student Res & Training STAR Program Augusta GA 30912 USA

Introduction At physiologic concentration in serum, the bile acid sodium deoxycholate (DC) induces survival and migration of breast cancer cells. Here we provide evidence of a novel mechanism by which DC reduces apoptosis that is induced by the sphingolipid ceramide in breast cancer cells. Methods Murine mammacarcinoma 4T1 cells were used in vitro to determine apoptosis and alteration of sphingolipid metabolism by DC, and in vivo to quantify the effect of DC on metastasis. Results We found that DC increased the number of intestinal metastases generated from 4T1 cell tumors grafted into the fat pad. The metastatic nodes contained slowly dividing cancer cells in immediate vicinity of newly formed blood vessels. These cells were positive for CD44, a marker that has been suggested to be expressed on breast cancer stem cells. In culture, a subpopulation (3 +/- 1%) of slowly dividing, CD44(+) cells gave rise to rapidly dividing, CD44(-) cells. DC promoted survival of CD44(+) cells, which was concurrent with reduced levels of activated caspase 3 and ceramide, a sphingolipid inducing apoptosis in 4T1 cells. Z-guggulsterone, an antagonist of the farnesoid-X-receptor, obliterated this anti-apoptotic effect, indicating that DC increased cell survival via farnesoid-X-receptor. DC also increased the gene expression of the vascular endothelial growth factor receptor 2 (Flk-1), suggesting that DC enhanced the initial growth of secondary tumors adjacent to blood vessels. The Flk-1 antagonist SU5416 obliterated the reduction of ceramide and apoptosis by DC, indicating that enhanced cell survival is due to Flk-1-induced reduction in ceramide. Conclusions Our findings show, for the first time, that DC is a natural tumor promoter by elevating Flk-1 and decreasing ceramide-mediated apoptosis of breast cancer progenitor cells. Reducing the level or effect of serum DC and elevating ceramide in breast cancer progenitor cells by treatment with Z-guggulsterone and/or vascular endothelial gro

关键词： Vascular Endothelial Growth Factor Ceramide Cancer Stem Cell additional data file SU5416

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