Complete Set Of Genes Research Articles

Complex microbiome underlying secondary and primary metabolism in the tunicate-Prochloron symbiosis.

The relationship between tunicates and the uncultivated cyanobacterium Prochloron didemni has long provided a model symbiosis. P. didemni is required for survival of animals such as Lissoclinum patella and also makes secondary metabolites of pharmaceutical interest. Here, we present the metagenomes, chemistry, and microbiomes of four related L. patella tunicate samples from a wide geographical range of the tropical Pacific. The remarkably similar P. didemni genomes are the most complex so far assembled from uncultivated organisms. Although P. didemni has not been stably cultivated and comprises a single strain in each sample, a complete set of metabolic genes indicates that the bacteria are likely capable of reproducing outside the host. The sequences reveal notable peculiarities of the photosynthetic apparatus and explain the basis of nutrient exchange underlying the symbiosis. P. didemni likely profoundly influences the lipid composition of the animals by synthesizing sterols and an unusual lipid with biofuel potential. In addition, L. patella also harbors a great variety of other bacterial groups that contribute nutritional and secondary metabolic products to the symbiosis. These bacteria possess an enormous genetic potential to synthesize new secondary metabolites. For example, an antitumor candidate molecule, patellazole, is not encoded in the genome of Prochloron and was linked to other bacteria from the microbiome. This study unveils the complex L. patella microbiome and its impact on primary and secondary metabolism, revealing a remarkable versatility in creating and exchanging small molecules.

Denitrification in Sinorhizobium meliloti

Denitrification is the complete reduction of nitrate or nitrite to N2, via the intermediates nitric oxide (NO) and nitrous oxide (N2O), and is coupled to energy conservation and growth under O2-limiting conditions. In Bradyrhizobium japonicum, this process occurs through the action of the napEDABC, nirK, norCBQD and nosRZDFYLX gene products. DNA sequences showing homology with nap, nirK, nor and nos genes have been found in the genome of the symbiotic plasmid pSymA of Sinorhizobium meliloti strain 1021. Whole-genome transcriptomic analyses have demonstrated that S. meliloti denitrification genes are induced under micro-oxic conditions. Furthermore, S. meliloti has also been shown to possess denitrifying activities in both free-living and symbiotic forms. Despite possessing and expressing the complete set of denitrification genes, S. meliloti is considered a partial denitrifier since it does not grow under anaerobic conditions with nitrate or nitrite as terminal electron acceptors. In the present paper, we show that, under micro-oxic conditions, S. meliloti is able to grow by using nitrate or nitrite as respiratory substrates, which indicates that, in contrast with anaerobic denitrifiers, O2 is necessary for denitrification by S. meliloti. Current knowledge of the regulation of S. meliloti denitrification genes is also included.

Genetic Architecture of Male Sterility and Segregation Distortion in Drosophila pseudoobscura Bogota–USA Hybrids

Understanding the genetic basis of reproductive isolation between recently diverged species is a central problem in evolutionary genetics. Here, I present analyses of the genetic architecture underlying hybrid male sterility and segregation distortion between the Bogota and USA subspecies of Drosophila pseudoobscura. Previously, a single gene, Overdrive (Ovd), was shown to be necessary but not sufficient for both male sterility and segregation distortion in F(1) hybrids between these subspecies, requiring several interacting partner loci for full manifestation of hybrid phenomena. I map these partner loci separately on the Bogota X chromosome and USA autosomes using a combination of different mapping strategies. I find that hybrid sterility involves a single hybrid incompatibility of at least seven interacting partner genes that includes three large-effect loci. Segregation distortion involves three loci on the Bogota X chromosome and one locus on the autosomes. The genetic bases of hybrid sterility and segregation distortion are at least partially--but not completely--overlapping. My results lay the foundation for fine-mapping experiments to identify the complete set of genes that interact with Overdrive. While individual genes that cause hybrid sterility or inviability have been identified in a few cases, my analysis provides a comprehensive look at the genetic architecture of all components of a hybrid incompatibility underlying F(1) hybrid sterility. Such an analysis would likely be unfeasible for most species pairs due to their divergence time and emphasizes the importance of young species pairs such as the D. pseudoobscura subspecies studied here.

Characterization of the lipopolysaccharide from Pasteurella multocida Heddleston serovar 9: Identification of a proposed bi-functional dTDP-3-acetamido-3,6-dideoxy- -D-glucose biosynthesis enzyme

Pasteurella multocida strains are classified into 16 different lipopolysaccharide (LPS) serovars using the Heddleston serotyping scheme. Ongoing studies in our laboratories on the LPS aim to determine the core oligosaccharide (OS) structures expressed by each of the Heddleston type strains and identify the genes and transferases required for the biosynthesis of the serovar-specific OSs. In this study, we have determined the core OS of the LPS expressed by the Heddleston serovar 9 type strain, P2095. Structural information was established by a combination of monosaccharide and methylation analyses, nuclear magnetic resonance spectroscopy and mass spectrometry revealing the following structure: . The serovar 9 OS contains an inner core that is conserved among P. multocida strains with an elaborate outer core extension containing rhamnose (Rha), a D-glycero-D-manno isomer of heptose, and the unusual deoxyamino sugar, 3-acetamido-3,6-dideoxy-α-D-glucose (Qui3NAc). Genetic analyses of the LPS outer core biosynthesis locus revealed that in addition to the glycosyltransferases predicted to transfer the sugars to the nascent LPS molecule, the locus also contained the complete set of genes required for the biosynthesis of the nucleotide sugar donors dTDP-Rha and dTDP-Qui3NAc. One of the genes identified as part of the dTDP-Qui3NAc biosynthesis pathway, qdtD, encodes a proposed bi-functional enzyme with N-terminal amino acid identity to dTDP-4-oxo-6-deoxy-D-glucose-3,4-oxoisomerase and C-terminal amino acid identity to dTDP-3-oxo-6-deoxy-α-D-glucose transacetylase.

The Complete Genome Sequence of Thermoproteus tenax: A Physiologically Versatile Member of the Crenarchaeota

Here, we report on the complete genome sequence of the hyperthermophilic Crenarchaeum Thermoproteus tenax (strain Kra1, DSM 2078T) a type strain of the crenarchaeotal order Thermoproteales. Its circular 1.84-megabase genome harbors no extrachromosomal elements and 2,051 open reading frames are identified, covering 90.6% of the complete sequence, which represents a high coding density. Derived from the gene content, T. tenax is a representative member of the Crenarchaeota. The organism is strictly anaerobic and sulfur-dependent with optimal growth at 86°C and pH 5.6. One particular feature is the great metabolic versatility, which is not accompanied by a distinct increase of genome size or information density as compared to other Crenarchaeota. T. tenax is able to grow chemolithoautotrophically (CO2/H2) as well as chemoorganoheterotrophically in presence of various organic substrates. All pathways for synthesizing the 20 proteinogenic amino acids are present. In addition, two presumably complete gene sets for NADH:quinone oxidoreductase (complex I) were identified in the genome and there is evidence that either NADH or reduced ferredoxin might serve as electron donor. Beside the typical archaeal A0A1-ATP synthase, a membrane-bound pyrophosphatase is found, which might contribute to energy conservation. Surprisingly, all genes required for dissimilatory sulfate reduction are present, which is confirmed by growth experiments. Mentionable is furthermore, the presence of two proteins (ParA family ATPase, actin-like protein) that might be involved in cell division in Thermoproteales, where the ESCRT system is absent, and of genes involved in genetic competence (DprA, ComF) that is so far unique within Archaea.

Embryonic expression of zebrafish MiT family genes tfe3b, tfeb, and tfec

The MiT family comprises four genes in mammals: Mitf, Tfe3, Tfeb, and Tfec, which encode transcription factors of the basic-helix-loop-helix/leucine zipper class. Mitf is well-known for its essential role in the development of melanocytes, however the functions of the other members of this family, and of interactions between them, are less well understood. We have now characterized the complete set of MiT genes from zebrafish, which totals six instead of four. The zebrafish genome contain two mitf (mitfa and mitfb), two tfe3 (tfe3a and tfe3b), and single tfeb and tfec genes; this distribution is shared with other teleosts. We present here the sequence and embryonic expression patterns for the zebrafish tfe3b, tfeb, and tfec genes, and identify a new isoform of tfe3a. These findings will assist in elucidating the roles of the MiT gene family over the course of vertebrate evolution.

Insight from the draft genome of Dietzia cinnamea P4 reveals mechanisms of survival in complex tropical soil habitats and biotechnology potential

The draft genome of Dietzia cinnamea strain P4 was determined using pyrosequencing. In total, 428 supercontigs were obtained and analyzed. We here describe and interpret the main features of the draft genome. The genome contained a total of 3,555,295 bp, arranged in a single replicon with an average G+C percentage of 70.9%. It revealed the presence of complete pathways for basically all central metabolic routes. Also present were complete sets of genes for the glyoxalate and reductive carboxylate cycles. Autotrophic growth was suggested to occur by the presence of genes for aerobic CO oxidation, formate/formaldehyde oxidation, the reverse tricarboxylic acid cycle and the 3-hydropropionate cycle for CO2 fixation. Secondary metabolism was evidenced by the presence of genes for the biosynthesis of terpene compounds, frenolicin, nanaomycin and avilamycin A antibiotics. Furthermore, a probable role in azinomycin B synthesis, an important product with antitumor activity, was indicated. The complete alk operon for the degradation of n-alkanes was found to be present, as were clusters of genes for biphenyl ring dihydroxylation. This study brings new insights in the genetics and physiology of D. cinnamea P4, which is useful in biotechnology and bioremediation.Electronic supplementary materialThe online version of this article (doi:10.1007/s10482-011-9633-7) contains supplementary material, which is available to authorized users.

Structure of fumarate hydratase from Rickettsia prowazekii, the agent of typhus and suspected relative of the mitochondria.

Rickettsiae are obligate intracellular parasites of eukaryotic cells that are the causative agents responsible for spotted fever and typhus. Their small genome (about 800 protein-coding genes) is highly conserved across species and has been postulated as the ancestor of the mitochondria. No genes that are required for glycolysis are found in the Rickettsia prowazekii or mitochondrial genomes, but a complete set of genes encoding components of the tricarboxylic acid cycle and the respiratory-chain complex is found in both. A 2.4 Å resolution crystal structure of R. prowazekii fumarate hydratase, an enzyme catalyzing the third step of the tricarboxylic acid cycle pathway that ultimately converts phosphoenolpyruvate into succinyl-CoA, has been solved. A structure alignment with human mitochondrial fumarate hydratase highlights the close similarity between R. prowazekii and mitochondrial enzymes.

Recovery and Characterization of Environmental Variants of Shigella flexneri from Surface Water in Bangladesh

Little is known about the distribution, survival, and transmission of Shigella in environmental surface waters. To gain more insight into the environmental biology of Shigella we isolated five bacterial strains serotyped as Shigella flexneri 2b from a freshwater lake in Bangladesh using a modified nutrient broth supplemented with nucleic acid bases. The biochemical properties of the isolates, including inability to ferment lactose and a negative lysine decarboxylase test, indicated common physiological characteristics with Shigella, but differed significantly from that of standard clinical strains. The isolates possessed the ipaH virulence gene and a megaplasmid, but lacked other Shigella-related virulence marker genes. Genetic fingerprinting and sequence analysis of housekeeping genes confirmed the strains as S. flexneri isolates. An apparent clonal origin of strains recovered with a one-year interval indicates a strong environmental selection pressure on Shigella for persistence in the freshwater environment. The lack of a complete set of virulence genes as well as uncommon biochemical properties suggest that these strains might represent a group of non-invasive and atypical environmental Shigella variants, with the potential for further elucidation of the survival mechanism, diversity, and emergence of virulent Shigella in tropical freshwater environments.

Agios' high metabolism

Agios Pharmaceuticals and collaborators at MIT and Harvard have used an RNAi-based in vivo screening technology to identify a target—PHGDH—that is involved in breast cancer. Now the team is screening the complete set of human metabolic genes to identify additional cancer targets.

Origin and evolution of TRIM proteins: new insights from the complete TRIM repertoire of zebrafish and pufferfish.

Tripartite motif proteins (TRIM) constitute a large family of proteins containing a RING-Bbox-Coiled Coil motif followed by different C-terminal domains. Involved in ubiquitination, TRIM proteins participate in many cellular processes including antiviral immunity. The TRIM family is ancient and has been greatly diversified in vertebrates and especially in fish. We analyzed the complete sets of trim genes of the large zebrafish genome and of the compact pufferfish genome. Both contain three large multigene subsets - adding the hsl5/trim35-like genes (hltr) to the ftr and the btr that we previously described - all containing a B30.2 domain that evolved under positive selection. These subsets are conserved among teleosts. By contrast, most human trim genes of the other classes have only one or two orthologues in fish. Loss or gain of C-terminal exons generated proteins with different domain organizations; either by the deletion of the ancestral domain or, remarkably, by the acquisition of a new C-terminal domain. Our survey of fish trim genes in fish identifies subsets with different evolutionary dynamics. trims encoding RBCC-B30.2 proteins show the same evolutionary trends in fish and tetrapods: they evolve fast, often under positive selection, and they duplicate to create multigenic families. We could identify new combinations of domains, which epitomize how new trim classes appear by domain insertion or exon shuffling. Notably, we found that a cyclophilin-A domain replaces the B30.2 domain of a zebrafish fintrim gene, as reported in the macaque and owl monkey antiretroviral TRIM5α. Finally, trim genes encoding RBCC-B30.2 proteins are preferentially located in the vicinity of MHC or MHC gene paralogues, which suggests that such trim genes may have been part of the ancestral MHC.

Profiling of the transcriptome of Porphyra yezoensis with Solexa sequencing technology

With high-throughput Solexa sequencing technology, we profiled Porphyra yezoensis transcriptomes from 8 different samples. More than 1200 megabases from 13333334 quality paired-end reads were generated, which were assembled into 31538 unigenes. Blast analysis showed that 56.7% unigenes were novel, which represented the specific genes of Porphyra and/or rhodophytes. Several hundreds of unigenes related to stress tolerance were discovered, including genes related to desiccation-(211) and high light-tolerance (31), flavonoid biosynthesis (10), reactive oxygen scavenging (48) and other stress-tolerance processes (208), which indicated there existed complex and diversity modes of stress tolerance in this species. A complete set of essential genes involved in the C3-(57) and C4-(44) carbon fixation pathway (except pyruvate phosphate dikinase) were discovered, which not only proved that they were actively transcribed but also clearly outlined the panoptic view of carbon fixation in Porphyra. Moreover, by statistically analyzing the types, proportions and frequencies of the interspersed repeats (TEs) and simple sequence repeats (SSRs), we discovered that the top three types of TEs were all retrotransposons and the trinucleotide was the absolute predominant type among SSRs, promoting our understanding of structural characteristics of the transcriptome. This study substantially improved the global view of the Porphyra genome and provided a valuable resource for future research.

The Sugarcane Genome Challenge: Strategies for Sequencing a Highly Complex Genome

Sugarcane cultivars derive from interspecific hybrids obtained by crossing Saccharum officinarum and Saccharum spontaneum and provide feedstock used worldwide for sugar and biofuel production. The importance of sugarcane as a bioenergy feedstock has increased interest in the generation of new cultivars optimised for energy production. Cultivar improvement has relied largely on traditional breeding methods, which may be limited by the complexity of inheritance in interspecific polyploid hybrids, and the time-consuming process of selection of plants with desired agronomic traits. In this sense, molecular genetics can assist in the process of developing improved cultivars by generating molecular markers that can be used in the breeding process or by introducing new genes into the sugarcane genome. For meeting each of these, and additional goals, biotechnologists would benefit from a reference genome sequence of a sugarcane cultivar. The sugarcane genome poses challenges that have not been addressed in any prior sequencing project, due to its highly polyploid and aneuploid genome structure with a complete set of homeologous genes predicted to range from 10 to 12 copies (alleles) and to include representatives from each of two different species. Although sugarcane’s monoploid genome is about 1 Gb, its highly polymorphic nature represents another significant challenge for obtaining a genuine assembled monoploid genome. With a rich resource of expressed-sequence tag (EST) data in the public domain, the present article describes tools and strategies that may aid in the generation of a reference genome sequence.

RepABC-based replication systems of Rhizobium leguminosarum bv. trifolii TA1 plasmids: Incompatibility and evolutionary analyses

Soil bacteria of the genus Rhizobium possess complex genomes consisting of a chromosome and in addition, often, multiple extrachromosomal replicons, which are usually equipped with repABC genes that control their replication and partition. The replication regions of four plasmids of Rhizobium leguminosarum bv. trifolii TA1 (RtTA1) were identified and characterized. They all contained a complete set of repABC genes. The structural diversity of the rep regions of RtTA1 plasmids was demonstrated for parS and incα elements, and this was especially apparent in the case of symbiotic plasmid (pSym). Incompatibility assays with recombinant constructs containing parS or incα demonstrated that RtTA1 plasmids belong to different incompatibility groups. Horizontal acquisition was plausibly the main contributor to the origin of RtTA1 plasmids and pSym is probably the newest plasmid of this strain. Phylogenetic and incompatibility analyses of repABC regions of three closely related strains: RtTA1, R. leguminosarum bv. viciae 3841 and Rhizobium etli CFN42, provided data on coexistence of their replicons in a common genomic framework.

The Genome of Erysipelothrix rhusiopathiae, the Causative Agent of Swine Erysipelas, Reveals New Insights into the Evolution of Firmicutes and the Organism's Intracellular Adaptations

Erysipelothrix rhusiopathiae is a Gram-positive bacterium that represents a new class, Erysipelotrichia, in the phylum Firmicutes. The organism is a facultative intracellular pathogen that causes swine erysipelas, as well as a variety of diseases in many animals. Here, we report the first complete genome sequence analysis of a member of the class Erysipelotrichia. The E. rhusiopathiae genome (1,787,941 bp) is one of the smallest genomes in the phylum Firmicutes. Phylogenetic analyses based on the 16S rRNA gene and 31 universal protein families suggest that E. rhusiopathiae is phylogenetically close to Mollicutes, which comprises Mycoplasma species. Genome analyses show that the overall features of the E. rhusiopathiae genome are similar to those of other Gram-positive bacteria; it possesses a complete set of peptidoglycan biosynthesis genes, two-component regulatory systems, and various cell wall-associated virulence factors, including a capsule and adhesins. However, it lacks many orthologous genes for the biosynthesis of wall teichoic acids (WTA) and lipoteichoic acids (LTA) and the dltABCD operon, which is responsible for d-alanine incorporation into WTA and LTA, suggesting that the organism has an atypical cell wall. In addition, like Mollicutes, its genome shows a complete loss of fatty acid biosynthesis pathways and lacks the genes for the biosynthesis of many amino acids, cofactors, and vitamins, indicating reductive genome evolution. The genome encodes nine antioxidant factors and nine phospholipases, which facilitate intracellular survival in phagocytes. Thus, the E. rhusiopathiae genome represents evolutionary traits of both Firmicutes and Mollicutes and provides new insights into its evolutionary adaptations for intracellular survival.

A microarray based expression profiling of paclitaxel and vincristine resistant MCF-7 cells

Resistance to the broad spectrum of chemotherapeutic agents in cancer cell lines and tumors has been called multiple drug resistance (MDR). In this study, the molecular mechanisms of resistance to two anticancer agents (paclitaxel and vincristine) in mammary carcinoma cell line MCF-7 were investigated. Drug resistant sublines to paclitaxel (MCF-7/Pac) and vincristine (MCF-7/Vinc) that were developed from sensitive MCF-7 cells (MCF-7/S) were used. cDNA microarray analysis was performed for the RNA samples of sensitive and resistant cells in duplicate experiments. GeneSpring GX 7.3.1 Software was used in data analysis. The results indicated that the upregulation of MDR1 gene is the dominating mechanism of the paclitaxel and vincristine drug resistance. Additionally the upregulation of the genes encoding the detoxifying enzymes (i.e. GSTP1) was observed. Significant downregulation of apoptotic genes (i.e. PDCD2/4/6/8) and upregulation of some cell cycle regulatory genes ( CDKN2A, CCNA2 etc.) was seen which may be in close relation to MDR in breast cancer. Drug resistant cancer cells exhibit different gene expression patterns depending on drug treatment, and each drug resistance phenotype is probably genetically different. Further functional studies are needed to demonstrate the complete set of genes contributing to the drug resistance phenotype in breast cancer cells.

A Platform for Processing Expression of Short Time Series (PESTS)

BackgroundTime course microarray profiles examine the expression of genes over a time domain. They are necessary in order to determine the complete set of genes that are dynamically expressed under given conditions, and to determine the interaction between these genes. Because of cost and resource issues, most time series datasets contain less than 9 points and there are few tools available geared towards the analysis of this type of data.ResultsTo this end, we introduce a platform for Processing Expression of Short Time Series (PESTS). It was designed with a focus on usability and interpretability of analyses for the researcher. As such, it implements several standard techniques for comparability as well as visualization functions. However, it is designed specifically for the unique methods we have developed for significance analysis, multiple test correction and clustering of short time series data. The central tenet of these methods is the use of biologically relevant features for analysis. Features summarize short gene expression profiles, inherently incorporate dependence across time, and allow for both full description of the examined curve and missing data points.ConclusionsPESTS is fully generalizable to other types of time series analyses. PESTS implements novel methods as well as several standard techniques for comparability and visualization functions. These features and functionality make PESTS a valuable resource for a researcher's toolkit. PESTS is available to download for free to academic and non-profit users at http://www.mailman.columbia.edu/academic-departments/biostatistics/research-service/software-development.

Genome-wide analysis of rice and Arabidopsis identifies two glyoxalase genes that are highly expressed in abiotic stresses

Glyoxalase pathway, ubiquitously found in all organisms from prokaryotes to eukaryotes, consists of glyoxalase I (GLY I) and glyoxalase II (GLY II) enzymes, which detoxify a cytotoxic molecule, methylglyoxal (MG). Increase in MG has been correlated with various diseases in humans and different abiotic stresses in plants. We have previously shown that overproduction of GLY I and/or GLY II enzymes in transgenic plants provide tolerance towards salinity and heavy metal stresses. We have identified nineteen potential GLY I and four GLY II proteins in rice and twenty two GLY I and nine GLY II proteins in Arabidopsis. An analysis of complete set of genes coding for the glyoxalase proteins in these two genomes is presented, including classification and chromosomal distribution. Expression profiling of these genes has been performed in response to multiple abiotic stresses, in different tissues and during various stages of vegetative and reproductive development using publicly available databases (massively parallel signature sequencing and microarray). AtGLYI8, OsGLYI3, and OsGLYI10 expresses constitutively high in seeds while AtGLYI4, AtGLYI7, OsGLYI6, and OsGLYI11 are highly stress inducible. To complement this analyses, qRT-PCR is performed in two contrasting rice genotypes, i.e., IR64 and Pokkali where OsGLYI6 and OsGLYI11 are found to be highly stress inducible.

Genome-Wide Analysis Reveals Frequent Inactivating Mutations of Acetyltransferase Genes In B-Cell Lymphoma

AbstractAbstract 474B cell non-Hodgkin lymphoma (B-NHL) comprises a variety of biologically and clinically distinct diseases whose pathogenesis is associated with largely unique genetic lesions affecting oncogenes and tumor suppressor genes. The identification of the complete set of genes and cellular pathways that are altered in the lymphoma cell is critical for a full understanding of the genesis and maintenance of these malignancies. Using genome-wide copy number analysis and high throughput whole exome sequencing, we have recently found that the two most common types of B-NHL, follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), are associated with frequent structural alterations inactivating the genes that encode CREBBP and, in a smaller fraction of cases, EP300, two highly related histone and non-histone acetyltranferases (HAT) that act as transcriptional coactivators in multiple signaling pathways. Overall, ~29% (n=39/134) of DLBCL and 32% (n=15/47) of FL samples display genomic deletions and/or somatic point mutations that remove or inactivate the HAT domain of CREBBP. In 19 additional cases (15 DLBCL and 4 FL), mutations and deletions were found in the EP300 gene, also predicting its functional loss. With few exceptions, structural alterations of CREBBP and EP300 were mutually exclusive, suggesting that inactivation of these loci is at least in part functionally equivalent. Thus, in total ~36% of all DLBCL (n=49/134) and at least 40% of FL cases (n=19/47) display genetic aberrations targeting acetyltransferase genes. Interestingly, while these lesions were observed in both DLBCL phenotypic subtypes, their frequency appears to be significantly higher in germinal center B cell type DLBCL, where they account for ~46% of the cases (n=30/65) as compared to 27% in activated B cell type DLBCL (n=11/69; p<0.01). CREBBP and EP300 structural alterations commonly affect a single allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. While the functional consequences of these lesions are likely to be broad on gene transcription, we demonstrate specific defects in the acetylation-mediated inactivation of the BCL6 onco-protein and activation of the p53 tumor suppressor, both of which contribute to transformation. These results identify CREBBP/EP300 alterations as a major pathogenetic mechanism shared by common forms of B-NHL, and have direct implications for the development of therapeutic regimens targeted to acetylation/deacetylation mechanisms. Disclosures:No relevant conflicts of interest to declare.

Transcriptomic landscape of the primitive streak

In birds and mammals, all mesoderm cells are generated from the primitive streak. Nascent mesoderm cells contain unique dorsoventral (D/V) identities according to their relative ingression position along the streak. Molecular mechanisms controlling this initial phase of mesoderm diversification are not well understood. Using the chick model, we generated high-quality transcriptomic datasets of different streak regions and analyzed their molecular heterogeneity. Fifteen percent of expressed genes exhibit differential expression levels, as represented by two major groups (dorsal to ventral and ventral to dorsal). A complete set of transcription factors and many novel genes with strong and region-specific expression were uncovered. Core components of BMP, Wnt and FGF pathways showed little regional difference, whereas their positive and negative regulators exhibited both dorsal-to-ventral and ventral-to-dorsal gradients, suggesting that robust D/V positional information is generated by fine-tuned regulation of key signaling pathways at multiple levels. Overall, our study provides a comprehensive molecular resource for understanding mesoderm diversification in vivo and targeted mesoderm lineage differentiation in vitro.