82 research outputs found
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 -â2Â 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: SociĂ©tĂ© Française de Biochimie et Biologie MolĂ©culaire ; French Research MinistryFunder: CancĂ©ropole Grand Ouest ; RĂ©gion Bretagne ; SociĂ©tĂ© Française dâHĂ©matologieFunder: Ligue RĂ©gionale contre le cancer ;ETV6-RUNX1 and RUNX1 directly promote RAG1 expression. ETV6-RUNX1 and RUNX1 preferentially bind to the â1200 bp enhancer of RAG1 and the â80 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 oestrogĂšnes
En rĂ©ponse Ă son environnement composĂ© de signaux endogĂšnes et exogĂšnes, une cellule doit pouvoir adapter son transcriptome, et cela Ă travers une modulation fine de l'expression de ses gĂšnes. Les mĂ©canismes permettant une telle adaptation reposent sur de multiples paramĂštres, entre autre l'organisation du gĂ©nome, que ce soit au niveau de sa sĂ©quence primaire ou de son organisation au sein de la chromatine qui est un support pour l'intĂ©gration de nombreuses informations (structurelles et Ă©pigĂ©nĂ©tiques). De plus, l'organisation tridimensionnelle du noyau cellulaire apporte des contraintes physiques et fonctionnelles qui contribuent Ă©galement Ă ces rĂ©gulations. Afin de comprendre comment toutes ces informations peuvent ĂȘtre intĂ©grĂ©es lorsqu'un signal rĂ©gule la transcription d'un ensemble de gĂšnes colinĂ©aires ( cluster de gĂšnes), nos Ă©tudes se sont focalisĂ©es sur la description et dissection des mĂ©canismes impliquĂ©s dans la rĂ©gulation coordonnĂ©es de gĂšnes ĆstrogĂ©no-dĂ©pendant par le rĂ©cepteur aux ĆstrogĂšnes (ER) et ses facteurs pionniers (FOXA1, FOXA2 et GATAs) dans des cellules cancĂ©reuses d'origine mammaire. Dans ce cadre, nous nous sommes plus particuliĂšrement intĂ©ressĂ©s au cluster TFF, situĂ© sur le bras long du chromosome 21, incluant le gĂšne modĂšle TFF1, en utilisant des techniques d'analyse Ă grande Ă©chelle (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. Ă©lectronique (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 diffĂ©renciation et de la reprogrammation cellulaire. Dans les cellules souches embryonnaires, des facteurs de transcription maĂźtres comme Pou5f1/Oct4, Nanog, Sox2 et Klf4 sont responsables d un rĂ©seau de rĂ©gulation qui va architecturer une chromatine aux propriĂ©tĂ©s pluripotentes. Au cours de la diffĂ©renciation, cette chromatine peut ĂȘtre modifiĂ©e de maniĂšre spĂ©cifique Ă chaque destinĂ©e cellulaire, afin de spĂ©cialiser et de restreindre le rĂ©pertoire de gĂšnes exprimĂ©s. Ce processus va notamment mettre en jeu l activation d enhancers liĂ©s par des facteurs de transcription exprimĂ©s de novo. Par des mĂ©thodes de cartographies Ă©pigĂ©nomiques dans diffĂ©rentes lignĂ©es cellulaires, nous avons observĂ© que l ADN des enhancers actifs est hypomĂ©thylĂ© et que la diffĂ©renciation cellulaire in vitro s accompagne d une hydroxymĂ©thylation de novo de certains enhancers activĂ©s.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
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