SORGOdb: Superoxide Reductase Gene Ontology curated DataBase

<p>Abstract</p> <p>Background</p> <p>Superoxide reductases (SOR) catalyse the reduction of superoxide anions to hydrogen peroxide and are involved in the oxidative stress defences of anaerobic and facultative anaerobic organisms. Genes encoding SOR were discovered recently and suffer from annotation problems. These genes, named <it>sor</it>, are short and the transfer of annotations from previously characterized neelaredoxin, desulfoferrodoxin, superoxide reductase and rubredoxin oxidase has been heterogeneous. Consequently, many <it>sor </it>remain anonymous or mis-annotated.</p> <p>Description</p> <p>SORGOdb is an exhaustive database of SOR that proposes a new classification based on domain architecture. SORGOdb supplies a simple user-friendly web-based database for retrieving and exploring relevant information about the proposed SOR families. The database can be queried using an organism name, a locus tag or phylogenetic criteria, and also offers sequence similarity searches using BlastP. Genes encoding SOR have been re-annotated in all available genome sequences (prokaryotic and eukaryotic (complete and in draft) genomes, updated in May 2010).</p> <p>Conclusions</p> <p>SORGOdb contains 325 non-redundant and curated SOR, from 274 organisms. It proposes a new classification of SOR into seven different classes and allows biologists to explore and analyze <it>sor </it>in order to establish correlations between the class of SOR and organism phenotypes. SORGOdb is freely available at <url>http://sorgo.genouest.org/index.php</url>.</p

Interplay between transcription regulators RUNX1 and FUBP1 activates an enhancer of the oncogene c-KIT and amplifies cell proliferation.

Runt-related transcription factor 1 (RUNX1) is a well-known master regulator of hematopoietic lineages but its mechanisms of action are still not fully understood. Here, we found that RUNX1 localizes on active chromatin together with Far Upstream Binding Protein 1 (FUBP1) in human B-cell precursor lymphoblasts, and that both factors interact in the same transcriptional regulatory complex. RUNX1 and FUBP1 chromatin localization identified c-KIT as a common target gene. We characterized two regulatory regions, at +700 bp and +30 kb within the first intron of c-KIT, bound by both RUNX1 and FUBP1, and that present active histone marks. Based on these regions, we proposed a novel FUBP1 FUSE-like DNA-binding sequence on the +30 kb enhancer. We demonstrated that FUBP1 and RUNX1 cooperate for the regulation of the expression of the oncogene c-KIT. Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. These results reveal a new mechanism of action of RUNX1 that implicates FUBP1, as a facilitator, to trigger transcriptional regulation of c-KIT and to regulate cell proliferation. Deregulation of this regulatory mechanism may explain some oncogenic function of RUNX1 and FUBP1

Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia.

Funder: FP7 People: Marie-Curie Actions; doi: http://dx.doi.org/10.13039/100011264; Grant(s): 291851BACKGROUND: B Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) is the most common pediatric cancer. Identifying key players involved in proliferation of BCP-ALL cells is crucial to propose new therapeutic targets. Runt Related Transcription Factor 1 (RUNX1) and Core-Binding Factor Runt Domain Alpha Subunit 2 Translocated To 3 (CBFA2T3, ETO2, MTG16) are master regulators of hematopoiesis and are implicated in leukemia. METHODS: We worked with BCP-ALL mononuclear bone marrow patients' cells and BCP-ALL cell lines, and performed Chromatin Immunoprecipitations followed by Sequencing (ChIP-Seq), co-immunoprecipitations (co-IP), proximity ligation assays (PLA), luciferase reporter assays and mouse xenograft models. RESULTS: We demonstrated that CBFA2T3 transcript levels correlate with RUNX1 expression in the pediatric t(12;21) ETV6-RUNX1 BCP-ALL. By ChIP-Seq in BCP-ALL patients' cells and cell lines, we found that RUNX1 is recruited on its promoter and on an enhancer of CBFA2T3 located - 2 kb upstream CBFA2T3 promoter and that, subsequently, the transcription factor RUNX1 drives both RUNX1 and CBFA2T3 expression. We demonstrated that, mechanistically, RUNX1 and CBFA2T3 can be part of the same complex allowing CBFA2T3 to strongly potentiate the activity of the transcription factor RUNX1. Finally, we characterized a CBFA2T3-mimicking peptide that inhibits the interaction between RUNX1 and CBFA2T3, abrogating the activity of this transcription complex and reducing BCP-ALL lymphoblast proliferation. CONCLUSIONS: Altogether, our findings reveal a novel and important activation loop between the transcription regulator CBFA2T3 and the transcription factor RUNX1 that promotes BCP-ALL proliferation, supporting the development of an innovative therapeutic approach based on the NHR2 subdomain of CBFA2T3 protein

ETV6-RUNX1 and RUNX1 directly regulate RAG1 expression: one more step in the understanding of childhood B-cell acute lymphoblastic leukemia leukemogenesis.

Funder: Société Française de Biochimie et Biologie Moléculaire ; French Research MinistryFunder: Cancéropole Grand Ouest ; Région Bretagne ; Société Française d’HématologieFunder: Ligue Régionale contre le cancer ;ETV6-RUNX1 and RUNX1 directly promote RAG1 expression. ETV6-RUNX1 and RUNX1 preferentially bind to the −1200 bp enhancer of RAG1 and the −80 bp promoter of RAG1 gene respectively, and compete for these bindings. ETV6-RUNX1 and RUNX1 induce an excessive RAG recombinase activity. ETV6-RUNX1 participates directly in two events of the multi-hit ALL leukemogenesis: as an initiating event and as an activator of RAG1 expression

Etude de l'expression des genes du recepteur aux oestrogenes et de la proopiomelanocortine dans le cerveau anterieur et l'hypophyse de truite arc-en-ciel (Oncorhynchus mykiss)

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : T 80383 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

DNA Demethylation by TET Proteins: A Potential Therapeutic Target in Cancer

International audienceDNA methylation in unique genomic regions like enhancers and promoters contributes to cell identity by silencing gene expression. Hence, establishment of cell-specific repertoires of active genes during cell differentiation or in response to extracellular signals may require erasure of this epigenetic mark. By their ability to hydroxylate the methyl group of 5-methylcytosine (5mC), Teneleven translocation (TET) proteins are part of the cellular machinery erasing DNA methylation through molecular mechanisms involving iterative oxidation of 5mC, base excision and repair. Here we review recent discoveries on TET functions and their role in regulating the genome activity to establish and maintain cell identity. We further describe how the TET-mediated processes are affected in cancer cells and propose possible strategies for the correction of these cancer-associated defects

Organisation de la chromatine et signalisation par les oestrogènes

En réponse à son environnement composé de signaux endogènes et exogènes, une cellule doit pouvoir adapter son transcriptome, et cela à travers une modulation fine de l'expression de ses gènes. Les mécanismes permettant une telle adaptation reposent sur de multiples paramètres, entre autre l'organisation du génome, que ce soit au niveau de sa séquence primaire ou de son organisation au sein de la chromatine qui est un support pour l'intégration de nombreuses informations (structurelles et épigénétiques). De plus, l'organisation tridimensionnelle du noyau cellulaire apporte des contraintes physiques et fonctionnelles qui contribuent également à ces régulations. Afin de comprendre comment toutes ces informations peuvent être intégrées lorsqu'un signal régule la transcription d'un ensemble de gènes colinéaires ( cluster de gènes), nos études se sont focalisées sur la description et dissection des mécanismes impliqués dans la régulation coordonnées de gènes œstrogéno-dépendant par le récepteur aux œstrogènes (ER) et ses facteurs pionniers (FOXA1, FOXA2 et GATAs) dans des cellules cancéreuses d'origine mammaire. Dans ce cadre, nous nous sommes plus particulièrement intéressés au cluster TFF, situé sur le bras long du chromosome 21, incluant le gène modèle TFF1, en utilisant des techniques d'analyse à grande échelle (ChIP-chip, ChIP-seq, 4C et analyses transcriptomiques).A given cell has to be able to adapt its fate and homeostasis in response to endogenous and exogenous signals. This adaptation occurs through finely tuned regulations of genes' expressions leading to the variation of their transcriptomes. Multiple parameters have to be integrated in order to provide such mechanisms of regulation. First, the primary sequence of the genome and its organization into chromatin are major regulatory components that harbor genetic, structural and epigenetic information. Second, the three-dimensional organization of the genome into the nucleus brings both physical and functional constraints that also contribute towards these regulatory processes. Here, we engaged a work aiming to understand and dissect how these several levels of information are integrated during the transcriptional regulation of colinear genes (cluster of genes) by the same signal. We took as a model the coordinated regulation of the estrogen-sensitive TFF cluster driven by the estrogen receptor (ER) and its pioneering factors (FOXA1, FOXA2 and GATAs) in mammary cancer cells. This cluster is located within the long arm of the chromosome 21, and contains the gene model termed TFF1. We used large-scale methods (ChIP-chip, ChIP-seq, 4C and microarray transcriptomic analyses) to decipher these dynamic mechanisms.RENNES1-Bibl. électronique (352382106) / SudocSudocFranceF

5-methylcytosine turnover: Mechanisms and therapeutic implications in cancer

International audienceDNA methylation at the fifth position of cytosine (5mC) is one of the most studied epigenetic mechanisms essential for the control of gene expression and for many other biological processes including genomic imprinting, X chromosome inactivation and genome stability. Over the last years, accumulating evidence suggest that DNA methylation is a highly dynamic mechanism driven by a balance between methylation by DNMTs and TET-mediated demethylation processes. However, one of the main challenges is to understand the dynamics underlying steady state DNA methylation levels. In this review article, we give an overview of the latest advances highlighting DNA methylation as a dynamic cycling process with a continuous turnover of cytosine modifications. We describe the cooperative actions of DNMT and TET enzymes which combine with many additional parameters including chromatin environment and protein partners to govern 5mC turnover. We also discuss how mathematical models can be used to address variable methylation levels during development and explain cell-type epigenetic heterogeneity locally but also at the genome scale. Finally, we review the therapeutic implications of these discoveries with the use of both epigenetic clocks as predictors and the development of epidrugs that target the DNA methylation/demethylation machinery. Together, these discoveries unveil with unprecedented detail how dynamic is DNA methylation during development, underlying the establishment of heterogeneous DNA methylation landscapes which could be altered in aging, diseases and cancer

Dynamique de méthylation et d hydroxyméthylation de l ADN des enhancers au cours de la différenciation cellulaire in vitro

Le transcriptome et le positionnement cis-tridimensionnel des domaines chromatiniens subissent conjointement des modifications profondes lors de la différenciation et de la reprogrammation cellulaire. Dans les cellules souches embryonnaires, des facteurs de transcription maîtres comme Pou5f1/Oct4, Nanog, Sox2 et Klf4 sont responsables d un réseau de régulation qui va architecturer une chromatine aux propriétés pluripotentes. Au cours de la différenciation, cette chromatine peut être modifiée de manière spécifique à chaque destinée cellulaire, afin de spécialiser et de restreindre le répertoire de gènes exprimés. Ce processus va notamment mettre en jeu l activation d enhancers liés par des facteurs de transcription exprimés de novo. Par des méthodes de cartographies épigénomiques dans différentes lignées cellulaires, nous avons observé que l ADN des enhancers actifs est hypométhylé et que la différenciation cellulaire in vitro s accompagne d une hydroxyméthylation de novo de certains enhancers activés.Transcriptome and cis-tridimensional positioning of chromatin domains undergo deep modifications during cell differentiation and reprogramming. In embryonic stem cells, master genes such as Pou5f1/Oct4, Nanog, Sox2 and Klf4 are implicated in a regulatory network which builds a pluripotent chromatin. This chromatin can be modified in a cell fate-specific manner during differentiation, allowing specialization and restriction of gene expression patterns. Specific enhancers bound by de novo expressed transcription factors become activated during this process. Using epigenomic mapping technologies in different cell lines, we observed that DNA of active enhancers is hypomethylated and that DNA of activated enhancers can be de novo hydroxymethylated during in vitro cell differentiation.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF