Дисертації з теми "Altérations de facteurs de transcription"
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Duployez, Nicolas. "Etude des altérations génomiques acquises dans les leucémies aiguës myéloïdes impliquant le core binding factor." Thesis, Lille 2, 2017. http://www.theses.fr/2017LIL2S037/document.
Повний текст джерелаRUNX1 and CBFB encode subunits of the core binding factor (CBF), a heterodimeric transcription factor required for the establishment of definitive hematopoiesis. Deregulation of the CBF is one of the most frequent aberrations in hematological malignancies. Since CBF disruption alone is insufficient to induce acute myeloid leukemia (AML) on its own, AML with CBF involvement is considered as a model of multistep leukemogenesis requiring additional genetic aberrations.Here, we focused on acute myeloid leukemia (AML) with t(8;21)/RUNX1-RUNX1T1 fusion and AML with inv(16)/CBFB-MYH11 fusion, reported together as CBF AML, as well as AML with germline RUNX1 mutation (defining the familial platelet disorder with propensity to develop leukemia or FPD/AML).In order to explore additional genomic aberrations, we performed comprehensive genetic profiling in CBF AML patients enrolled in the French trials ELAM02 (0-18 years) and CBF2006 (18-60 years) using both high-throughput sequencing (n=215) and single nucleotide polymorphism-array (n=198). In addition, we sequenced samples from 25 individuals with FPD/AML (15 pedigrees) diagnosed between 2005 and 2014 at thrombocyto-penic stage and during leukemic progression.In CBF AML, mutations in genes activating tyrosine kinase (TK) signaling were frequent in both subtypes as previously described by others. By contrast, we found mutations in genes encoding chromatin modifiers or members of the cohesin complex with high frequencies in t(8;21) AML (41% and 18% respectively) while they were nearly absent in inv(16) AML. Interestingly, such mutations were associated with a poor prognosis in patients with TK mutations suggesting synergic cooperation between these events. Other events included ZBTB7A and DHX15 mutations in t(8;21) AML (20% and 6% respectively) and FOXP1 deletions or truncating mutations in inv(16) AML (7%). Finally, we described CCDC26 disruption as a possible new lesion associated with aberrant TK signaling in this particular subtype of leukemia (4.5% of CBF AML).In FPD/AML, mutational analysis revealed the acquisition of a second event involving RUNX1 in all patients with AML including somatic mutation of the second allele or duplication of the germline RUNX1 mutation through copy-neutral loss of heterozygosity and trisomy 21. In clinical practice, we suggest that the occurrence of two different RUNX1 mutations or a single RUNX1 mutation with a variant allele frequency higher than 50% in a patient with AML should alert about the possibility of FPD/AML
Brunet, Julie. "Altérations épigénétiques et rôle du facteur de transcription UHRF1 dans les cellules-hôtes infectées par Toxoplasma gondii." Strasbourg, 2010. https://publication-theses.unistra.fr/public/theses_doctorat/2010/BRUNET_Julie_2010.pdf.
Повний текст джерелаToxoplasmosis, caused by a parasite, Toxoplasma gondii, is one of the most common infections in France:about 50% of the adult population is infected and it is estimated that 200,000-300,000 new infections occur each year, 15-20% which are symptomatic. The severity of infection is due to the risk of fetal transmission of the parasite in cases of infection during pregnancy and the risk of reactivation in the case of immunosuppression. There is no efficient treatment for the intracellular forms of the parasite and no vaccine. T. Gondii is an obligate intracellular parasite that interferes with the molecular signaling pathways of host cells and alters several physiological processes such as differentiation, apoptosis and proliferation. The transcription factor UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) is a key cell cycle regulator. It’s also a "methyl-CpG-binding protein” that gives it a crucial role in the replication of the epigenetic code. The molecular mechanisms by which the parasite affects the host cell remain poorly understood. We observed that infection with T. Gondii leads to an inhibition of proliferation of host cells due to cell cycle arrest in G2 phase. This results in a decrease of expression of cyclin B and a sharp increase in UHRF1 in host cells. Inhibition of UHRF1 by SiRNA in host cells induces a significant decrease in parasite growth. We observed an increase in binding of UHRF1 to cyclin B promoter during infection with T. Gondii. UHRF1 could be responsible for the repression of cyclin B gene, leading to cell cycle arrest. T. Gondii is able to modulate gene expression by interfering with two important epigenetic modifications, methylation and histone modifications. UHRF1 is a transcription factor that connects these two epigenetic modifications. This would make UHRF1 a powerful tool that would allow the parasite to exploit the genome of the host cell. Activating UHRF1 involved the transcription factor NF-kB and a factor based on the parasite rhoptries
Ruiz, Emmanuelle. "Coopération entre les inducteurs de l’EMT (EMT-TF/miRNA) et les altérations oncogéniques dans la tumorigenèse mammaire." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10069.
Повний текст джерелаCancer cells are able to reactivate the Epithelio-Mesenchymal Transition (EMT), an embryonic mechanism, to acquire mobility and dedifferentiation capacities. EMT leads to a genetic reprogramming with the reactivation of EMT inductors, mainly transcription factors (EMT-TF) and the inhibition of miRNA. Otherwise, oncogenic stresses are essentials to tumor progression. The aim of my thesis project was to have a better understanding about the cooperation between events of genetic reprogramming occurring during EMT and oncogenic stresses during mammary tumor transformation. First, a screening based on oncogenic cooperation in soft agar assay, between EMT-TFs and oncogenic stresses was performed. Following a bioinformatics analysis, different EMT-TFs signatures associated with an oncogenic stress were identified. Thus, for example, the expression of EMT-TF ZEB1 and GSC were associated with the deletion of tumor suppressor gene PTEN to transform immortalized mammary epithelial cells. An immunohistochemistry analysis on a set of 558 triple negative breast cancers validated in vivo the presence of a correlation between the expressions of GSC and PTEN. However, this association seems to be more complex. Indeed, the expression of GSC is negatively associated with the nuclear expression of PTEN while it’s positively associated with the cytoplasmic expression of PTEN. Finally, an analysis of public metadata on cancer samples as TCGA or METABRIC is ongoing to validate these in vitro signatures and wider to determine how EMT or EMT-TFs associated signatures correlate with classical oncogenic pathways.Secondly, an in silico analysis, from predictive algorithms of miRNA targets, was performed to select miRNA able to inhibit the expression of several EMT-TFs. Two miRNA (miR-495 and miR-590-3p) were identified targeting several members of four principal’s families of EMT-TFs (FOXC, Snail, bHLH and ZEB). In vitro tests were realized to validate these regulations identifying Slug as a target of miR-590-3p. Moreover, these miRNAs expression in mammary cell lines is negatively correlated with EMT-TFs expression and EMT markers. A treatment with TGF-, a major EMT inductor, decreases their expression, potentially meaning that these miRNA can negatively regulate EMT. In parallel, several EMT-TFs are able to repress the expression of miR-590-3p, acting directly on its promotor, thus creating feedback loops. Functional studies using stable expression vector of miR-590-3p suggest a secondary role of this miRNA in the regulation of EMT because miR-590-3p deregulates EMT secondary markers as N-Cadherin. Functions restauration studies are planned to determine how important these feedback loops in mammary tumor progression are. To open the project, expression of these identified miRNA will be correlated with EMT-TF associated signatures and with classical oncogenic pathways to determine the link between these three components in mammary tumorigenesis. My thesis works are shown that there is an interactome between EMT inductors, oncogenic stresses and miRNA during human mammary transformation
Jamrog, Laura. "Impact des altérations génétiques de PAX5 sur le développement de la lignée lymphoïde B et dans la leucémogenèse des LAL-B." Electronic Thesis or Diss., Toulouse 3, 2021. http://www.theses.fr/2021TOU30306.
Повний текст джерелаThe PAX5 (Paired boX 5) gene encodes a key transcription factor crucial for B-cell differentiation. We showed that the two PAX5 isoforms are differentially regulated but have equivalent function during early B-cell differentiation. Indeed, PAX5A and PAX5B isoforms can both induce B-cell program but may have functional differences after B-cell activation. The tight control of their expression may thus reflect a way to finely tune PAX5 dosage during B-cell differentiation process. PAX5 is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and is the main target of a wide diversity of somatic alterations in childhood and adult BCP-ALL, occurring in one third of sporadic cases. However, the role of PAX5 fusion proteins in BCP-ALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human BCP-ALL that juxtaposed PAX5 to the coding sequence of elastin (ELN). To study the function of the resulting PAX5-ELN fusion protein in BCP-ALL development, we generated a mouse model in which the PAX5-ELN transgene is expressed specifically in B cells. PAX5-ELN-expressing mice efficiently developed BCP-ALL phenotype with a penetrance of 80%. Leukemic transformation was associated with clonal Immunoglobulin gene rearrangement and recurrent secondary mutations in Ptpn11, Kras, Pax5, and Jak3 genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrated that PAX5-ELN impairs B-cell development in vitro and in vivo and induces an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Our molecular and computational approaches identified PAX5-ELN-regulated candidate genes that establish the molecular bases of the preleukemic state to drive BCP-ALL initiation. In conclusion, our study provides a new in vivo model recapitulating the multistep leukemogenesis process of human BCP-ALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development. Furthermore, there is increasing evidence for an inherited genetic basis of susceptibility to childhood BCP-ALL. In this context, four unrelated families with childhood BCP-ALL expressing heterozygous PAX5 germline point mutations were recently reported: the recurrent mutation PAX5 G183S affecting the octapeptide domain of PAX5 has been described in three families while PAX5 R38H affecting its DNA-binding paired domain has been identified in another one. We strengthen the hypothesis of inherited character of familial BCP-ALL with the description of three novel familial BCP-ALL cases in related patients that express the germline PAX5 R38H mutation. To uncover the intrinsic effect of PAX5 R38H mutant in B-cell development, we performed in vitro, and in vivo functional assays combined with a gene expression analysis, based on a retroviral complementation approach. Our results indicated that PAX5 R38H mutant acts as a strong hypomorphic variant that fails to drive B-cell differentiation and does not exert a dominant-negative effect on wild-type PAX5. Syngeneic transplantation of PAX5 R38H-expressing cells demonstrated maintenance of engraftment capacity and led to development of BCP-ALL phenotype in mice. Our transcriptomic analysis of these PAX5 R38H-expressing cells showed that PAX5 R38H drastically alters the pattern of expression of PAX5 target genes but also revealed a distinct molecular signature specific to PAX5 R38H. Together with previous unrelated family study, our observations allow to establish the recurrence of the germline PAX5 R38H mutation associated with BCP-ALL. Our data also highlight the importance of transcriptional dysregulation in leukemogenesis of familial BCP-ALL, particularly of genes involved in B-cell differentiation
Sérandour, Aurélien. "Dynamique de méthylation et d’hydroxyméthylation de l’ADN des enhancers au cours de la différenciation cellulaire in vitro." Rennes 1, 2011. http://www.theses.fr/2011REN1S074.
Повний текст джерелаTranscriptome 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
Dubaele, Sandy. "Importance de la sous-unité XPD pour l'architecture et les activités du facteur de transcription-réparation TFIIH." Université Louis Pasteur (Strasbourg) (1971-2008), 2003. http://www.theses.fr/2003STR13136.
Повний текст джерелаFan, Jun. "Single-molecule basis of transcription-coupled DNA repair." Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC213.
Повний текст джерелаThe DNA in living cells is constantly threatened by damages from both endogenous and exogenous agents, which can threaten genomic integrity, block processes of replication, transcription and translation and have also genotoxic effects. In response to the DNA damage challenge, organisms have evolved diverse surveillance mechanisms to coordinate DNA repair and cell-cycle progression. Multiple DNA repair mechanisms, discovered in both prokaryotic and eukaryotic organisms, bear the responsibility of maintaining genomic integrity; these mechanisms include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) and double strand break repair (DSBR). Transcription-coupled DNA repair (TCR) is a specialized NER subpathway characterized by enhanced repair of the template strand of actively transcribed genes as compared to the classical global genome repair (GGR) subpathway of NER which does not distinguish between template and non-template strands. TCR achieves specialization via the involvement of RNA polymerase (RNAP) and the Mfd (Mutation Frequency Decline) protein, also known as TRCF (transcription repair coupling factor). TCR repair initiates when RNAP stalls at a DNA lesion on the transcribed strand and serves as the da mage sensor. The stalled RNAP must be displaced so as to make the lesion accessible to downstream repair components. E. Coli Mfd translocase participates in this process by displacing stalled RNAP from the lesion and then coordinating assembly of the UvrAB(C) components at th( damage site. Recent studies have shown that after binding to and displacing stalled RNAP, Mfd remains on the DNA in the form of a stable, translocating complex with evicted RNAP. So as to understand how UvrAB(C) are recruited via the Mfd-RNAP complex, magnetic trapping of individual, damaged DNA molecules was employed to observe-in real-time this multi¬component, multi-step reaction, up to and including the DNA incision reaction by UvrC. It was found that the recruitment of UvrA and UvrAB to the Mfd-RNAP complex halts the translocating complex and then causes dissolution of the complex in a molecular "hand-off" with slow kinetics Correlative single-molecule nanomanipulation and fluorescence further show that dissolution of the complex leads to loss of not only RNAP but also Mfd. Hand-off then allows for enhanced incision of damaged DNA by the UvrC component as compared to the equivalent single-moleculE GGR incision reaction. A global model integrating TCR and GGR components in repair was proposed, with the overall timescales for the parallel reactions provided
Benko, Sabina. "Altérations génomiques à grande distance d'éléments non-codants conservés et dérégulation d'expression tissu-spécifique au locus SOX9." Paris 5, 2010. http://www.theses.fr/2010PA05T039.
Повний текст джерелаSQX9 is a major developmental gene mapping to a vast gene desert that encompasses its regulatory domain. The SOX9 gene coding equence mutations result in campomelic dysplaisa (CD), a complex polymalformative syndrome. We showed that alterations of non-coding sequences (translocations, deletions or point mutations) at the SOX9 locus result in isolated CD endophenotypes namely Pierre Robin sequence (iPRS) and disorders of sex developpement (iDSD). Both in vitro and in vivo studies indicate that those alterations, located at great distance with respect to SOX9 coding sequences (>1,2Mb/iPRS; >500kb/iDSD), comprise regions conserved throughout the evolution that function as regulatory elements driving tissue specific gene expression of SOX9. We suggest that alterations identified in iPRS and iDSD patients represent a tissue specific loss of SOX9 expression in the mandibular mesenchyme or the developing gonad respectively, while other territories of normal SOX9 expression remain intact
Zerdoumi, Yasmine. "Analyse fonctionnelle des mutations constitutionnelles hétérozygotes du gène suppresseur de tumeur TP53 dans le contexte génétique des patients atteints du syndrome de Li-Fraumeni." Rouen, 2016. http://www.theses.fr/2016ROUES035.
Повний текст джерелаLi-Fraumeni Syndrome (LFS), resulting from heterozygous germline mutations of TP53, is one of the most severe hereditary cancer syndromes. In order to determine the molecular basis of the clinical gradient of germline TP53 mutations, we studied the functional consequences of the different types of TP53 mutations in the genetic context of the patients, and we showed that TP53 missense mutations with dominant-negative effect alter the p53 transcriptional response to DNA damage more drastically than null mutations. These results indicate that the impact of the mutations on p53 transcriptional response to DNA damage in LFS lymphocytes can be considered as an endophenotype of the clinical severity of germline TP53 mutations. The use of the simple p53 functional assay allowed us to confirm these observations on a large number of mutations. ChIP-Seq analysis performed on lymphocytes derived from TP53 wild-type control subject and LFS patient with TP53 dominant-negative missense, showed that the drastic alteration of p53 transcriptional response to DNA in LFS lymphocytes harboring dominant negative missense mutations, is explained by a massive and global alteration of p53 DNA binding. In order to determine the causative role of chemotherapies in the appearance of secondary tumours in LFS, we developed a new genotoxicity assay, named the p53 genotoxicity assay. This assay allowed us to show that most of the drugs commonly used in cancer treatment, except the microtubule poisons, are highly genotoxic. Thus, in TP53 mutation carriers, germline TP53 mutations represent a genetic permissive context facilitating the malignant transformation of cells in which DNA damage has occurred
Gosselin, Karo. "Étude de l'implication du stress oxydant induit par les facteurs Rel/NF-kappaB dans la sénescence et l'émergence tumorale." Lille 1, 2005. https://pepite-depot.univ-lille.fr/RESTREINT/Th_Num/2005/50376-2005-75.pdf.
Повний текст джерелаNugues, Anne-Lucie. "Altération du ripoptosome dans la leucémie aiguë myéloïde." Phd thesis, Université du Droit et de la Santé - Lille II, 2013. http://tel.archives-ouvertes.fr/tel-01018661.
Повний текст джерелаLefort, Karine. "Réponse cellulaire spécifique du mélanocyte humain aux ultraviolets B : implication du facteur de transcription N-oct3." Lyon 1, 2002. http://www.theses.fr/2002LYO1T115.
Повний текст джерелаIgnacimouttou, Cathy. "Etude du rôle d'ETO2 et GLIS2 dans la transformation par la fusion ETO2-GLIS2 dans les leucémies aiguës mégacaryoblastiques pédiatriques." Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC082.
Повний текст джерелаAcute megakaryoblastic leukemia (AML-M7) represent a rare subtype of acute myeloid leukemia mainly diagnosed in young children. In almost all cases, M7 are characterized by expression of oncogenic fusion including ETO2-GLIS2 fusion and for which the molecular mechanisms of transformation were unknown. During this work, I characterized the relative contribution of ETO2 and GLIS2 in the transformation of hematopoietic cells by the fusion ETO2- GLIS2. I have shown that the GLIS2 function induces megakaryocytic phenotype and both ETO2 and GLIS2 contribute to the increase of self-renewing progenitors induced by the fusion. Moreover, I have shown that ETO2-GLIS2 dimerizes and interacts with wild type ETO2. Specific interference with a peptide corresponding to the NHR2 domain of ETO2 inhibited the oligomerization, reversed transcriptional signature of the fusion, increased the megakaryocytic differentiation of leukemic blasts and abrogated leukemia development in vivo of M7 patients cells expressing ETO2-GLIS2. Megakaryocyte and erythrocyte lineages proximity and the presence of genetic alterations found in the ETO2 megakaryoblastic leukemia (AML-M7) and erythroid (AML-M6) led me to develop a xenograft strategy with AML-M6 patients samples in immunodeficient mice. This allowed me to characterize their genetic alterations to achieve functional analyzes. Preliminary results show that in most cases, AML-M6 have phenotypes similar to normal erythroid differentiation steps. Moreover, several mutations of genes coding for chromatin regulators, splice genes, cohesins and transcription factors suggest that the molecular mechanisms are common during leukemic transformation
Rosenberg, Charles Dan. "Altération du facteur de transcription cyclic adenosine monophosphate responsive element binding protein [CREB] au cours de la tumorigenèse du cortex surrénalien." Paris 6, 2003. http://www.theses.fr/2003PA066293.
Повний текст джерелаHarir, Noria. "Propriétés oncogéniques des facteurs de transcription STAT5." Amiens, 2007. http://www.theses.fr/2007AMIED001.
Повний текст джерелаIltis, Izarn. "Rôles transcriptionnels des facteurs NER." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00849966.
Повний текст джерелаGiuliano, Sandy. "MITF contrôle la voie de réponse de dommage à l'ADN et la sénescence des cellules de mélanome." Nice, 2011. http://www.theses.fr/2011NICE4025.
Повний текст джерелаMalignant melanoma is an aggressive cancer known for its notorious resistance to most current therapies. The basic helix loop helix Microphtalmia transcription factor (MIRF) is the master regulator determining the identity and properties of the melanocyte lineage and is regarded as a lineage-specific “oncogene” that plays a critical role in the pathogenesis of melanoma. Here we report that depletion of MITF in melanoma cells triggers a lineage-restricted program of senescence characterized by typical morphologic and biochemical changes associated with a sustained growth arrest. Our findings demonstrate that MIRF silenced cells engage a DNA damage response (DDR) that is critically required for senescence entry. More importantly, engagement of the DDR machinery allows MITF to control the endogenous level of the tumor suppressor p53 and we show that p53 loss antagonizes the senescence program. By combining ChIP-seq and RNA-seq analyses, we identify that MITF regulates a set of genes required for DNA replication, repair and mitosis. Particularly we identified survivin a chromosomal passenger protein as a new target of MIRF. Down regulation of several of these genes trigger mitotic defects suggesting that similar effects should be observed upon MITF inhibition. We show that MITF or surviving depletion triggers aberrant karyokinesis and cytokinesis and promotes cellular senescence. We propose a model of mitotic errors caused by inhibition of surviving after invalidation of MITF which lead to DNA damage and a program of senescence. These findings shows that MITF acts an anti-senescence factor and reveal a lineage-specific control of cell division through surviving regulation providing new avenues for therapeutic intervention in melanoma
Vigneault, François. "Régulation génique par les facteurs de transcription NFI." Thesis, Université Laval, 2008. http://www.theses.ulaval.ca/2008/25325/25325.pdf.
Повний текст джерелаCarillo, Serge. "Dégradation des facteurs de transcription nucléaires FOS et JUN." Montpellier 2, 1994. http://www.theses.fr/1994MON20235.
Повний текст джерелаLainé, Jean-Philippe. "TFIIH and transcription coupled repair." Université Louis Pasteur (Strasbourg) (1971-2008), 2005. http://www.theses.fr/2005STR13195.
Повний текст джерелаAccurate coordination of the various events that maintain the integrity of the genome and regulate its expression is a prerequisite for differentiation, proliferation and cell life. The interconnection of such cellular processes is highlighted by the multi-functional complex TFIIH. Originally identified as a RNA polymerase II transcription factor, TFIIH also participates in the DNA nucleotide excision repair (NER) reaction. Ve focused my work on the functional/structural contribution within the complex of p52, one of the ten subunits of TFIIH, the link between transcription and NER, and the role of TFIIH in both. I first demonstrated that the carboxy-terminal of p52 is important for stabilizing the anchoring of XPB, another subunit of TFIIH, within the complex. This interaction is important for the role of XPB in the DNA opening step during transcription initiation. Then I focused my attention on the mechanism linking transcription to NER. I was able to show that a stalled elongating RNA polymerase II is able to recruit the repair factors at the site of the lesion and promote the removal of the DNA patch containing the lesion
Rojas, Andrés. "Le facteur de transcription TFIIA : localisation et interactions." Sherbrooke : Université de Sherbrooke, 1999.
Знайти повний текст джерелаWydau-Dematteis, Sandra. "Etude de deux facteurs sigma secondaires de Lactococcus lactis." Paris 11, 2005. http://www.theses.fr/2005PA112065.
Повний текст джерелаThe expression of the genes encoding the sigma factors ComX and SigX in Lactococcus lactis differs during growth : the expression peak of comX corresponds at the onset of the stationary phase and the one of sigX takes place in exponential phase. The aim of this work is to understand the role of these sigma factors in Lactococcus lactis. ComX is homologous to sigma inducing the transcription of the late genes of natural competence in several streptococci. L. Lactis is not listed as a natural competent bacterium but its genome includes some genes encoding a potential late system. Two types of ComX (ComXIL and ComXMG) were identified in lactococci that diverge by amino-acid substitutions. The overeexpression of ComXIL allows the induction of the transcription of the late genes. A conserved motif (« cin-box ») is found upstream of these genes and could correspond to the sequence recognised by ComXIL to initiate the transcription. The « cin-box » revealed itself to be very conserved in lactococci, including in the strains with a ComX of type ComXMG. The purification of ComXIL, ComXMG and of the RNA polymerase has been undertaken to study the affinity of the ComX for the « cin-box » and for the RNA polymerase. To identify the regulon controlled by SigX, two approaches are used by comparing two conditions : overexpression or not of sigX. The first approach was the proteomic. This study did not reveal any targets of SigX. The second approach is the transcriptomic. The first results indicate that SigX may control the transcription of genes encoding membrane proteins. This study should lead to the identification of the role of SigX in L. Lactis
Hamard, Pierre Jacques. "Contribution à l'étude du facteur de transcription ATF7." Université Louis Pasteur (Strasbourg) (1971-2008), 2005. https://publication-theses.unistra.fr/restreint/theses_doctorat/2005/HAMARD_Pierre_Jacques_2005.pdf.
Повний текст джерелаATF7 proteins, which are members of the b-Zip family of transcription factors, are able to bind ATF/CRE sequences (TGACGTCA) within different early adenoviral or cellular promoters. ATF7 can interact with the family of Jun/Fos oncoproteins and modulate their activities. To get an insight into the transactivation mechanism mediated by ATF7, we analyzed its relations with hsTAFs proteins, which are components of several multiproteic complexes like TFIID. Our results show that transactivation by ATF7 is specifically mediated by hsTAF12, mainly by its 20-kDa isoform. Moreover, ATF7 and hsTAF12 interact in vivo : the integrity of the ATF7 amino-terminal activation domain and of the hsTAF12 "histone-fold" domain is required for this interaction. We show that hsTAF12 mediated transactivation is specifically inhibited by hsTAF4 (its heterodimerization partner within TFIID), and not by hsTAF4b, a tissue-specific hsTAF4 homolog. Ubc9, a protein involved in the SUMOylation pathway, was found among the proteins interacting with ATF7 and modulating its activity. We have identified a consensus SUMOylation site within the N-terminal part of ATF7 and demonstrate that ATF7 is SUMOylated both by in vitro and in vivo experiments. Moreover, our results reveal that the intracellular localization of ATF7 is affected by its SUMOylation : ATF7 is found in the nucleus only in a de-SUMOylated form ; the cytoplasmic SUMOylation of ATF7 likely induces its sequestration at the level of the nuclear pore complexes (NPC). Using immunohistochemistry assays, we observe a colocalization between ATF7 and RanBP2, a protein of the NPC, which is an E3 ligase of the SUMOylation pathway. Accordingly, RanBP2 is able to stimulate ATF7 SUMOylation in vitro. This NPC targeting seems to influence ATF7 transactivation activity as an ATF7 mutant, whose SUMOylation is impaired, is more active than its SUMOylated counterpart. These results correlate with our chromatin-immunoprecipitation (ChIP) experiments, which show that the occupancy of a target promoter by ATF7 is highest in the presence of the unSUMOylated protein
Hichri, Imène. "Identification et caractérisation fonctionnelle de gènes régulateurs de la voie de biosynthèse des flavonoïdes chez la Vigne." Thesis, Bordeaux 1, 2009. http://www.theses.fr/2009BOR13875/document.
Повний текст джерелаPhenolic compounds, and more specifically flavonoids (flavonols, condensed tannins and anthocyanins), are key components of the grapevine and wine quality. Because of their antioxidant activities, these compounds are of interest in pharmacological and cosmetic industries, as well as being beneficial to the human diet. Previous work on model plants showed that the flavonoid pathway was mainly regulated by the MYB and bHLH transcription factors, and WD40 proteins. In the grapevine (Vitis vinifera L.), only MYB regulators have been identified until now, and no bHLH or WD40 have been characterised. In this work, several approaches were used to identify new transcription factors involved in grapevine flavonoid biosynthesis. Firstly, the VvMYB5b protein was used as a bait in a large scale two hybrid experiment in yeast (Saccharomyces cerevisiae). Secondly, the promoter of the VvDFR gene, coding a central enzyme of the flavonoid pathway, was chosen to conduct a large scale one hybrid experiment, also in yeast. Finally, a “gene candidate” approach allowed identification of the bHLH transcription factors VvMYC1 and VvMYCA1. VvMYCA1 expression profile in berry skin and seeds correlates with condensed tannins synthesis, whereas VvMYC1 transcript accumulation in these tissues and the grapevine inflorescence correlates with condensed tannins, anthocyanins and flavonols accumulation. In yeast, VvMYC1 could physically interact with different MYB partners regulating the anthocyanin or the condensed tannins biosynthesis. This interaction was confirmed by transient promoter assays in grape cell suspensions, where co-expression of VvMYC1 with specific MYB partners activated the UFGT and ANR promoters. Likewise, this interaction induced anthocyanin accumulation in grape cells, as well as in tobacco leaves and Arabidopsis. Eventually, additional transient promoter assays revealed that VvMYC1 is involved, with VvMYBPA1, in feedback regulation of its own expression
Lauzier, Marie-Claude. "Régulation de l'activité des facteurs de transcription induits par l'hypoxie." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26884/26884.pdf.
Повний текст джерелаHypoxia-inducible transcription factors (HIF) are decisive elements in the transcriptional regulation of numerous genes expressed in conditions of hypoxic stress. In addition to their roles in many physiological and cellular processes, HIF are also involved in diverse pathological situations. Obligate heterodimers composed of a constitutive β subunit and of an oxygen tension-regulated α subunit, these transcription factors are mainly regulated by the hydroxylation and subsequent degradation of the α subunit. In hypoxia, this degradation mechanism is inhibited, resulting in HIF complex formation and binding to specific DNA sequences. The work presented in this thesis aims to elucidate regulatory mechanisms involved in HIF activation during hypoxia or in normal oxygen conditions. In the Results section, you will find a study devoted to HIF activation by angiotensin II (Ang II) in vascular smooth muscle cells. Specifically, the role of receptor tyrosine kinase transactivation on HIF activation was evaluated along with a description of HIF-1’s role in smooth muscle cells biology. Next, an inhibitor of matrix metalloproteases, BiPS, will be presented as a novel and potent HIF activator. This unexpected effect may have important implications for the use of this compound for its angiostatic potential in cancer treatment. In addition, BiPS and derivative molecules could also have strong therapeutic potential in ischemic diseases. Finally, you will find a section devoted to the study of a new transcriptional repressor of HIF complexes, the histone acetyltransferase bound to ORC-1, HBO1. Surprisingly, HBO1 represses the activity of HIF complexes by a mechanism independent of the availability of the α subunits, but dependent on a chromatin remodelling event. In conclusion, this thesis highlights new regulatory mechanisms responsible for HIF activation. Considering the important physiological roles of HIF complexes and their implications in the pathogenesis of different diseases, these studies increase the available knowledge concerning the biological functions of these complexes and could contribute to the development of more effective and safe therapeutic tools.
Harroch, Sheila. "Les facteurs de transcription impliqués dans l'action de l'interleukine-6." Toulouse 3, 1994. http://www.theses.fr/1994TOU30211.
Повний текст джерелаPuranik, Sriharsha. "Élucidation structurale des facteurs de transcription végétaux à domaines MADS." Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV083/document.
Повний текст джерелаVirtually all terrestrial habitats are dominated by angiosperms, or flowering plants. Their success in colonizing new habitats and supplanting other species is due to the advent of a complex reproductive structure – the flower. The flower unites the male and female organs into one compact structure and encloses the seed. Flowering plants are not only the dominant type of land plants, but also are the primary source of food and habitat for all animals, including humans. In evolutionary terms, flowers are considered a recent development and have been a subject of speculation from the time of Charles Darwin who termed the dominant rise and diversification of flowering plants as “an abominable mystery”* due to the lack of a smooth transition from non-flowering to flowering plants in the fossil record. With the sequencing of multiple genomes from gymnosperms (non-flowering seed plants), basal angiosperms and higher flowering plants, certain gene families have been identified which play a central role in the development and evolution of the flower. My research focuses on one such family of high-level regulators, the MADS transcription factor (TF) family. This TF family helps to orchestrate flower development among other functions. As such, there is great interest in understanding the molecular mechanisms of the MADS family and how these proteins are able to control complex reproductive pathways.This project integrates different biophysical techniques including x-ray crystallography, small angle x-ray scattering (SAXS) and atomic force microscopy (AFM) to investigate protein-protein and protein-DNA interactions of MADS TFs. No studies to date have investigated the molecular mechanisms of MADS TFs using this integrated structural approach.One important hurdle in the study of the MADS TFs has been recombinant protein expression and purification. In this project, recombinant purification protocols for several full length MADS TFs were established, allowing the structural and biochemical characterisation of the proteins. The crystal structure of the oligomerisation domain of the MADS family protein SEPALLATA3 (SEP3) is presented and used as a template for understanding the oligomerisation patterns of the larger family and the molecular basis for protein-protein interactions. Investigation of solution structures, derived from SAXS studies, of AGAMOUS (AG) and SHORT VEGETATIVE PHASE (SVP) along with biochemical characterisation of their oligomerisation states are also presented.In order to study protein-DNA interactions, complementary methods were used. An important putative property of the MADS TFs is their ability to change the structure of DNA through the formation of DNA loops. MADS TFs are hypothesized to oligomerise and bind DNA at two different sites, potentiating looping of DNA. Using AFM, the first direct evidence of DNA looping by SEP3 is described. The DNA binding characteristics of SVP were studied using electrophoretic mobility shift assay (EMSA), microscale thermophoresis (MST) and AFM. Unlike SEP3, SVP is dimeric and thus exhibits different DNA-binding patterns.The data presented here provide an atomic and structural basis for MADS TF function. Based on this work, we now are beginning to understand some of the oligomerisation and DNA-binding specificity determinants. These studies demonstrate how the MADS TFs oligomerise and the results show that we can disrupt oligomerisation and potentially DNA-binding very specifically through the introduction of point mutations. Future work will investigate the in vivo consequences of altered oligomerisation and how this affects different developmental programs in plant reproduction and floral organ morphogenesis.*Letter from Charles Darwin to Joseph Dalton Hooker, written 22 July 1879 (Source: Cambridge University Library DAR 95: 485 – 488) (Friedman, 2009b)
Gueroult, bellone Marion. "Signatures nucléotidiques de l'activité des enhancers développementaux chez l'ascidie Ciona intestinalis." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTS029.
Повний текст джерелаEnhancers are crucial elements for the control of gene expression during embryonic development. The ascidian Ciona intestinalis offers unique experimental features to study these cis-regulatory sequences: enhancers are generally small and compact and their activity can be tracked at the single cell level thanks to the invariant cell lineage of ascidian embryos.Previous work identified two independent signatures associated with enhancer activity: the presence of specific transcription factors binding sites (TFBS) and a global dinucleotide signature along enhancers (Khoueiry, 2010). Although they correlate with enhancer activity, these signatures are insufficient to identify enhancer sequences from their sole sequence. During my thesis, I used a well-characterized early neural Ciona enhancer, the a-element of the Otx gene, as a model enhancer. This small (55pb) enhancer, is bound by GATA-a and ETS1/2 and is activated by the FGF pathway. To better understand the determinants of early neural enhancer activity, I tested the impact of point mutations affecting the affinity of the a-element TFBS for their binding TF and of the randomization of the spacer sequences that separate the TFBS in four ETS and GATA binding site clusters.Our results suggest at least two levels of cis-regulatory control: spatiotemporal specificity of enhancer activity is encoded in the identity of TF-binding sites, while the level of enhancer activity is set both by the affinity of TFs for their binding sites and by the composition of the spacer sequences. A surprisingly high number of variants of the a-element with randomized spacers are active, always in the same cell lineages as the WT. These variants, however, display a wide range of activity levels. This effect is also observed when the spacers in another active ETS/GATA cluster are randomized. Randomization of the spacers can even confer enhancer activity to a large fraction of inactive cluster variants. Consistent with their early neural activity and with the presence of ETS- and GATA-binding sites, these variants are, like the a-element, responsive to the FGF neural inducer.We could not link the action of the spacers on enhancer activity to any simple nucleotide or dinucleotide sequence features and it currently remains unclear why it is so easy to create a synthetic enhancer while most putative genomic ETS/GATA clusters are inactive. Using in vitro transcription factor binding assays, we showed that randomization of spacer sequences can affect TF binding to the a-element without changing the primary sequence of the binding site, and that extended minimal TFBS do not always recapitulate binding to the whole element. These results suggest that the physical structure of the DNA helix around the binding sites may play an important role in the control of enhancer activity
Guillet, Christelle. "Altérations de la réponse du métabolisme des protéines musculaires aux facteurs anaboliques au cours du vieillissement." Clermont-Ferrand 1, 2003. http://www.theses.fr/2003CLF1MM21.
Повний текст джерелаVerreman, Kathye. "Identification et caractérisation de nouveaux partenaires du facteur de transcription ERM." Thesis, Lille 1, 2009. http://www.theses.fr/2009LIL10057/document.
Повний текст джерелаERM is an ETS transcription factor which belongs to the PEA3 group and is involved in several processes such as migration and dissemination during organogenesis and cancer development. Regulation of its transcriptional activity requires post-translational modifications and interactions with partner proteins. In order to identify new ERM partners, we have developed various affinity chromatography techniques to isolate new potential partners. Among these candidates, CoAA (CoActivator Activator), MED23 and MED25 directly interact with ERM.MED23 and MED25 are subunits of the mediator. The mediator is a 30 sub-units multi-protein complex which mediates signals from transcription factors bound at upstream promoter elements or enhancers to RNA polymerase II and the general initiation factors bound at the core promoter. We found that MED23 and MED25 interact with ERM in vitro and in vivo and are required for transcriptional activation induced by ERM. However, these sub-units display various ability to recruit the mediator on ERM in vitro. The heterogeneous nuclear ribonucleoprotein-like protein CoAA regulates gene expression and RNA splicing. We demonstrated that ERM interacts in vitro and in vivo with CoAA. ERM transcriptional activity is enhanced upon CoAA overexpression and is decreased by CoAA knock-down. We demonstrated that CoAA modulates ERM transcriptional activity by decreasing sumoylated ERM levels. This work demonstrated new ways to regulate the activity of ERM and the two other PEA3 group members. The molecular mechanisms involved in the modulation of PEA3 member activity by these partners remain to be clarified
Borensztein, Maud. "Rôle des gènes Myod et Igf2 dans le développement embryonnaire murin." Paris 6, 2010. http://www.theses.fr/2010PA066374.
Повний текст джерелаMaire, Cecile. "Fonction des facteurs de transcription Olig1 et Olig2 dans les cellules souches neurales du système nerveux central : Etude d'un modèle de souris transgéniques d'expression inductible." Paris 5, 2007. http://www.theses.fr/2007PA05D030.
Повний текст джерелаOlig1 and Olig2 are b-HLH transcription factors involved in oligodendrocyte development in the central nervous system. My project aims to analyse the effect of Olig gene over-expression in neural stem cells. Therefore, I designed and analyzed transgenic mice models with inducible expression of Olig genes in nestin+ neural stem/progenitor cells (Tet-On system). At embryonic stages, forced expression of Olig1 and Olig2 leads to ectopic expression of oligodendrocyte markers. Moreover, Olig2 over-expression decreased V3 interneuron specification. At postnatal stage Olig2 over-expression in germinative area induced earlier myelination and astrocyte specification in corpus callosum. These transgenic mice provide a useful model to test whether forced expression of Olig genes represents a possible strategy to enhance remyelination in demyelinating disease such as multiple sclerosis
LAVIGNE, ANNE-CLAIRE. "Clonage et caracterisation des facteurs constitutifs du complexe de transcription tfiid." Université Louis Pasteur (Strasbourg) (1971-2008), 1998. http://www.theses.fr/1998STR13150.
Повний текст джерелаSève, Michel. "Les facteurs de transcription de la famille Sp : structure et fonctionnalité." Université Joseph Fourier (Grenoble), 1999. http://www.theses.fr/1999GRE18014.
Повний текст джерелаCastinetti, Frédéric. "Facteurs de transcription à l'homéodomaine : du modèle murin à l'hypopituitarisme humain." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX20681/document.
Повний текст джерелаHypopituitarism is defined by one or several pituitary deficiencies. Congenital hypopituitarism is mostly due to transcription factors mutations. Our aims were to try to better identify some of the mechanisms involved in pituitary ontogenesis and pituitary diseases, mainly pituitary deficiencies: new pathways, new transcription factors, new mutations. - First we identified novel mechanisms necessary for the differenciation of the Pou1f1 lineages (ie somatolactotroph and thyrotroph cells). The role of TLE co-repressors is crucial, as they are able by themselves to inhibit the stimulatory actions of PROP1 on POU1F1 promoter. This is necessary to obtain a correct timing of differentiation during pituitary development (Carvalho, Brinkmeier, castinetti et al., Molecular Endocrinology, 2010). - Second, we showed the roles of 2 transcription factors, PITX2 and ISL1, in thyrotrophs maintenance and function. By using a new cre recombinase driven by the TSHb promoter, we managed to inactivate each of these transcription factors in the thyrotrophs. Inactivation of PITX2 led to a partial thyrotroph deficiency, counterbalanced by an overexpression of PITX1 (Castinetti et al., Molecular Endocrinology, submitted). Inactivation of ISL1 led to a complete thyrotroph deficiency (Castinetti et al., Molecular Endocrinology, in preparation). - Finally, we reported 1 new mutation of the LIM transcription factor LHX4, responsible for combined pituitary hormone deficiencies in a family. New phenotypic traits will help the physician improve the way to select which patients to screen for LHX4 mutations (Castinetti, Saveanu et al., JCEM, 2008)
Delaporte, Virginie. "Caractérisation génomique des facteurs de transcription de la famille GT chez Arabidopsis thaliana : cas des facteurs GT-1 et GT-21b." Amiens, 2004. http://www.theses.fr/2004AMIE0421.
Повний текст джерелаPasquet, Stéphanie. "Etude de la régulation transcriptionnelle du gène alpha-tropomyosine dans les cellules musculaires." Bordeaux 2, 2003. http://www.theses.fr/2003BOR21036.
Повний текст джерелаWe have studied the transcriptional regulation of alpha-tropomyosin (α-TM) gene, in smooth, skeletal and cardiac muscle cells in culture. The regulatory sequences, C-rich and MCAT enhance transcription of the α-TM gene in the three muscle types. TEF-1 trans-factor plays a major role in the transcriptional regulation in the three muscle types, by binding to MCAT sequence. SRF factor seems to be involved, directly and indirectly, in the transcription activation of the gene. SRF could act indirectly in smooth and cardiac muscle cells, by enhancing TEF-1 binding, and directly in skeletal muscle cells, by binding to a CarG box. The role of TEF-1 and SRF factors could be related to their subcellular localization in smooth muscle cells
Leurent, Claire. "Etude structurale des complexes contenant des TAFs, TFIID et TFTC, par microscopie électronique et analyse d'images de molécules isolées." Université Louis Pasteur (Strasbourg) (1971-2008), 2002. http://www.theses.fr/2002STR13185.
Повний текст джерелаTFIID is a big complex, which plays a key role in regulation of transcription of class II genes. Its binding to the ADN promoter allows the recruitment and the assembly of the whole preinitiation complex. TFIID is composed of TBP (TATA Binding Protein) associated to 14 TAFs (TBP-Associated Factors). We obtained 3D structures of human and yeast TFIID using electron microscopy and single molecule image analysis. The human and yeast complexes appeared very similar in size and in shape and were organised in three domains forming a molecular clamp with a size suitable to accommodate a double stranded DNA molecule. Surprisingly, the TFTC complex (TBP-Free TAF Containing Complex), which is able to initiate transcription in the same manner than TFIID and contain 8 TAFs, but which doesn't contain TBP, also organised in molecular clamp very similar to TFIID. Finally, we mapped the 9 Histone Fold Domain-containing TAFs (HFD-TAFs), reported to heterodimerize in 5 pairs in coexpressions experiments and in pair-wise interactions. The immunolocations show that HFD-partners colocalise but that each HFD-TAF was found in two different lobes of the yeast TFIID structure revealing an unexpected and novel molecular organisation of TFIID
Guilhem, Ducléon Frédéric. "Caractérisation d'un nouveau système d'expression de petits ARN interférents et son application à l'analyse du facteur de transcription Bdp1 dans la transcription par l'ARN polymérase III ex vivo." Bordeaux 2, 2007. http://www.theses.fr/2007BOR21504.
Повний текст джерелаRobert, François. "Rôle du facteur de transcription TFIIF dans la structure du complexe transcriptionnel de l'ARN polymérase II." Sherbrooke : Université de Sherbrooke, 1999.
Знайти повний текст джерелаChabrat, Audrey, and Audrey Chabrat. "Role of Lmx1a and Lmx1b transcription factors in post-mitotic midbrain dopaminergic neurons." Doctoral thesis, Université Laval, 2016. http://hdl.handle.net/20.500.11794/28203.
Повний текст джерелаLmx1a et Lmx1b sont des facteurs de transcription connus pour leur rôle au cours du développement des neurones dopaminergiques du mésencéphale (mDA). Ils ont été montrés comme essentiels à chacune des étapes de différentiation des progéniteurs en neurones dopaminergiques matures. Des études récentes ont également mis en évidence l'importance de ces deux facteurs de transcription dans les neurones dopaminergiques chez l'adulte. Lmx1a/b sont impliqués dans la régulation de gènes mitochondriaux ainsi que dans l'autophagie. Cependant, jusqu'à présent, rien n'est connu sur le rôle de Lmx1a/b dans les neurones dopaminergiques post-mitotiques. Le but de cette thèse est d'élucider le rôle de Lmx1a/b dans les neurones dopaminergiques matures. L'analyse des projections axonales dopaminergiques de souris doubles conditionnelles mutantes (cKO) pour Lmx1a/b a mis en évidence un défaut de guidage axonal confirmant le rôle essentiel de ces deux facteurs de transcription dans la formation des circuits dopaminergiques. Afin d’identifier précisément les molécules impliquées dans la régulation du système dopaminergique des techniques adaptées doivent être développées pour déterminer les principaux acteurs régulés par Lmx1a/b. À cette fin, nous avons mis au point une technique de marquage immunohistochimique rapide de la tyrosine hydroxylase (TH, enzyme nécessaire à la synthèse de la dopamine) sur des sections de mésencéphale de souris afin de délimiter la région d’intérêt. Par la suite, nous utilisons une technique de microdissection au laser afin de spécifiquement récolter les cellules dopaminergiques du mésencéphale pour réaliser un profil d'expression génique. Un premier article de méthodologie a été publié concernant cette technique. Cette procédure menée sur des souris cKO pour Lmx1a et Lmx1b et leurs contrôles associés a permis de mettre en évidence des gènes régulés par Lmx1a et Lmx1b tels que Plxnc1. Plxnc1 est une protéine de guidage axonal ayant pour ligand la sémaphorine 7a (Sema7a). Afin d'observer si la régulation de Plxnc1 par Lmx1a/b est à l'origine du défaut de guidage axonal observé chez les souris cKO pour Lmx1a/b, nous avons réalisé une analyse in vitro de l’effet de la Sema7a sur les axones d'explants mDA. Notre étude a montré un effet chimiorépulsif de la Sema7a pour les axones des neurones mDA exprimant Plxnc1. De plus, l’étude de souris Sema7a KO montre une augmentation de l’innervation DA dans la partie dorsale du striatum, partie exprimant Sema7a chez des souris contrôles. Ce phénotype met en évidence une chimiorépulsion induite par l’interaction Sema7a/Plxnc1. L’étude de souris surexprimant Plxnc1 a, quant à elle, montré une perte d’innervation DA dans la partie dorsale du striatum. En effet, la majorité des cellules du mésencéphale se mettent à exprimer Plxnc1, les rendant ainsi sensibles à la chimiorépulsion induite par Sema7a. L’ensemble de ces résultats met en évidence l’importance de la régulation de la protéine de guidage axonal Plxnc1 par Lmx1a/b pour l'innervation des cibles du mésencéphale. La répression de Plxnc1 dans les neurones dopaminergiques de la substance noire pars compacta (SNpc) semble nécessaire à l’innervation du striatum dorsal riche en Sema7a. Cette étude est la première à identifier les bases moléculaires du guidage axonal expliquant la ségrégation des voies mDA nigrostriée et mésolimbique, et devrait contribuer à améliorer l'efficacité des thérapies cellulaires pour la maladie de Parkinson. Un second article sera soumis prochainement sur le rôle des facteurs de transcription Lmx1a/b dans les neurones dopaminergiques post-mitotiques du mésencéphale. La principale caractéristique histopathologique de la maladie de Parkinson est la dégénérescence des neurones mDA de la SNpc. La thérapie de remplacement cellulaire utilisant des neurones dopaminergiques nouvellement générés à partir de cellules souches représente une thérapie prometteuse. Cependant, la mauvaise innervation des neurones nouvellement greffés limite le succès des études de transplantation. L’identification de facteurs régulant la connectivité des neurones mDA devient primordiale pour élucider les mécanismes impliqués dans la mise en place du système dopaminergique. C'est pourquoi, dans une derniere partie, afin d'illustrer cette possibilité d'amélioration d'une thérapie de remplacement cellulaire, j’ai réalisé l’implantation de cellules souches différenciées en neurones dopaminergiques dans un modèle de souris lésées à la 6-hydroxydopamine (6OHDA). Les cellules nouvellement réimplantées sont de type SNpc, en raison de l'infection par un vecteur viral induisant l'inhibition de l'expression de Plxnc1.
Lmx1a and Lmx1b are transcription factors known for their role in the development of midbrain dopamine neurons (mDA). They were shown as essential for each stage of differentiation from progenitors to mature dopaminergic neurons. Recent studies have also highlighted the importance of these two transcription factors in dopaminergic neurons in adult mice. Lmx1a/b are involved in the regulation of mitochondrial genes and in autophagy. Although some evidence suggest that they could be involved in the formation of mDa circuit formation, their role in post-mitotic mDA neurons remains unknown. The aim of this thesis is to elucidate the role of Lmx1a/b in post-mitotic dopaminergic neurons. Analysis of dopaminergic axonal projections of double conditional mutant (cKO) mice for Lmx1a/b showed an axon guidance defect confirming the essential role of these transcription factors in the formation of dopaminergic circuits. In order to precisely identify the molecules involved in the regulation of the dopamine system, suitable techniques must be developed to identify the main genes that are regulated by Lmx1a/b. To this end we developed a new technique allowing gene profiling of brain sub-population. By combining rapid immunolabeling of mDA neurons with laser capture microdissection we manage to extract RNA from two sub-regions of mDA neurons such as ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc). The advantage of this technique is to compare quickly the regulation of genes expression by studying controls and mutant mice. A first methodological article has been published regarding this procedure. We then applied this technique on cKO mice for Lmx1a/b and their associated controls to identify genes regulated by Lmx1a and Lmx1b. Among these genes, we identified Plxnc1, an axon guidance receptor for the semaphorin 7a (Sema7a). In order to verify whether the regulation of Plxnc1 by Lmx1a/b is at the origin of the axon guidance defect observed in double conditional mutant for Lmx1a/b, we have made an in vitro analysis of the effect of Sema7a on mDA explants. Our study showed a chemorepulsive effect of Sema7a on Plxnc1 positives axons. In addition, the study of knockout mice for Sema7a shows an increase of DA innervation in the dorsal part of the striatum which is the region expressing Sema7a in control mice. This phenotype reveals a chemorepulsion induced by Sema7a/Plxnc1 interaction. The study of mice overexpressing Plxnc1 shows a loss of DA innervation in the dorsal striatum. Indeed, by overexpressing Plxnc1, the majority of midbrain cells begin to express this axon guidance protein instead of only mDA neurons from the VTA. Thus, all mDA neurons including neurons from the SNpc express Plxnc1 making them sensitive to Sema7a. This interaction Sema7a/Plxnc1 leads to a chemorepulsion of axons guided away from the dorsal striatum. Overall these results highlight the importance of the regulation of the axon guidance protein Plxnc1 by Lmx1a/b for the innervation of midbrain targets. The repression of Plxnc1 expression in dopaminergic neurons of the SNpc appears necessary for the innervation of dopaminergic axons in the dorsal striatum, rich in Sema7a. This study is the first to identify the molecular basis of the development of the dopaminergic system explaining the segregation of the nigrostriatal and mesolimbic pathways. These results should help to improve the effectiveness of cell therapies for Parkinson's disease. A second article will be submitted soon about the role of Lmx1a/b transciption factors in post-mitotic midbrain dopaminergic neurons. The main histopathological feature of Parkinson's disease (PD) is the degeneration of SNpc neurons. The cell replacement therapy using newly generated dopaminergic neurons from stem cells represents a promising therapy. However, a poor innervation of the newly grafted neurons limits the success of transplantation studies. The identification of factors regulating neuronal connectivity of mDA neurons becomes essential to elucidate the mechanisms involved in the establishment of the dopaminergic system. Therefore, in a final section of this thesis, I report preliminary study about cell replacement therapy in PD mouse model. I differentiated DA neurons from stem cells, knock-down Plxnc1 expression and performed grafting in 6-hydroxydopamine (6OHDA) mouse model to illustrate the possibility of improving a cell replacement therapy.
Lmx1a and Lmx1b are transcription factors known for their role in the development of midbrain dopamine neurons (mDA). They were shown as essential for each stage of differentiation from progenitors to mature dopaminergic neurons. Recent studies have also highlighted the importance of these two transcription factors in dopaminergic neurons in adult mice. Lmx1a/b are involved in the regulation of mitochondrial genes and in autophagy. Although some evidence suggest that they could be involved in the formation of mDa circuit formation, their role in post-mitotic mDA neurons remains unknown. The aim of this thesis is to elucidate the role of Lmx1a/b in post-mitotic dopaminergic neurons. Analysis of dopaminergic axonal projections of double conditional mutant (cKO) mice for Lmx1a/b showed an axon guidance defect confirming the essential role of these transcription factors in the formation of dopaminergic circuits. In order to precisely identify the molecules involved in the regulation of the dopamine system, suitable techniques must be developed to identify the main genes that are regulated by Lmx1a/b. To this end we developed a new technique allowing gene profiling of brain sub-population. By combining rapid immunolabeling of mDA neurons with laser capture microdissection we manage to extract RNA from two sub-regions of mDA neurons such as ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc). The advantage of this technique is to compare quickly the regulation of genes expression by studying controls and mutant mice. A first methodological article has been published regarding this procedure. We then applied this technique on cKO mice for Lmx1a/b and their associated controls to identify genes regulated by Lmx1a and Lmx1b. Among these genes, we identified Plxnc1, an axon guidance receptor for the semaphorin 7a (Sema7a). In order to verify whether the regulation of Plxnc1 by Lmx1a/b is at the origin of the axon guidance defect observed in double conditional mutant for Lmx1a/b, we have made an in vitro analysis of the effect of Sema7a on mDA explants. Our study showed a chemorepulsive effect of Sema7a on Plxnc1 positives axons. In addition, the study of knockout mice for Sema7a shows an increase of DA innervation in the dorsal part of the striatum which is the region expressing Sema7a in control mice. This phenotype reveals a chemorepulsion induced by Sema7a/Plxnc1 interaction. The study of mice overexpressing Plxnc1 shows a loss of DA innervation in the dorsal striatum. Indeed, by overexpressing Plxnc1, the majority of midbrain cells begin to express this axon guidance protein instead of only mDA neurons from the VTA. Thus, all mDA neurons including neurons from the SNpc express Plxnc1 making them sensitive to Sema7a. This interaction Sema7a/Plxnc1 leads to a chemorepulsion of axons guided away from the dorsal striatum. Overall these results highlight the importance of the regulation of the axon guidance protein Plxnc1 by Lmx1a/b for the innervation of midbrain targets. The repression of Plxnc1 expression in dopaminergic neurons of the SNpc appears necessary for the innervation of dopaminergic axons in the dorsal striatum, rich in Sema7a. This study is the first to identify the molecular basis of the development of the dopaminergic system explaining the segregation of the nigrostriatal and mesolimbic pathways. These results should help to improve the effectiveness of cell therapies for Parkinson's disease. A second article will be submitted soon about the role of Lmx1a/b transciption factors in post-mitotic midbrain dopaminergic neurons. The main histopathological feature of Parkinson's disease (PD) is the degeneration of SNpc neurons. The cell replacement therapy using newly generated dopaminergic neurons from stem cells represents a promising therapy. However, a poor innervation of the newly grafted neurons limits the success of transplantation studies. The identification of factors regulating neuronal connectivity of mDA neurons becomes essential to elucidate the mechanisms involved in the establishment of the dopaminergic system. Therefore, in a final section of this thesis, I report preliminary study about cell replacement therapy in PD mouse model. I differentiated DA neurons from stem cells, knock-down Plxnc1 expression and performed grafting in 6-hydroxydopamine (6OHDA) mouse model to illustrate the possibility of improving a cell replacement therapy.
Pflieger, Aude. "Etude des interactions de PTF (Proximal sequence element-binding Transcription Factor) et de leurs foctions au sein de la transcription par L'ARN polymérase III humaine." Bordeaux 2, 2006. http://www.theses.fr/2006BOR21389.
Повний текст джерелаIn order to study the structure and the function of the complex PTF within the human RNA polymerase III transcription basal system but also in order to widen knowledge outside this system and to highlight regulators of the RNA polymerase III transcription, I undertook by double-hybrid the study of the interaction partners of the complex sub-units. I showed in vitro an interaction between sub-units PTFα and PTFβ and between proteins PTFα and Brf2. I proposed a potential regulator of the RNA polmerase III transcription. A model of regulation utilizing this protein posed at the laboratory seems to be confirmed. The results obtained are very encouraging and important since we know that during cellular transformation the RNA polymerase III transcription is down-regulated. However complementary experiments are necessary to confirm this model
Soyer, Jessica. "Caractérisation de la régulation de l’expression des gènes codant des effecteurs chez Leptosphaeria maculans." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA112266.
Повний текст джерелаLeptosphaeria maculans is an ascomycete belonging to the Dothideomycete class and is part of a species complex showing different level of adaptation toward oilseed rape. Within this species complex, Lmb is responsible for the most damaging disease of this crop: “stem canker”. Lmb presents a complex life cycle during which it alternates between different life styles and nutritional strategies underlying the involvement of precise regulatory networks for gene expression to rapidly adapt to new conditions. The sequencing of the Lmb genome has revealed an unusual structure, alternating two types of regions, GC- and AT-isochores. While GC-isochores are gene-rich, AT-isochores are gene-poor and have several characteristics of heterochromatin (they are rich in transposable elements and present a lower rate of recombination compared to GC-isochores). Although gene-poor, AT-isochores are “ecological niches” for effector genes as 20% of the genes in these regions encode for putative effectors against only 4% of the genes in GC-isochores. Effector-encoding genes located in AT-isochores present a different transcriptional behavior compared to those located in GC-isochores: a very low expression in axenic culture and a drastic increase in expression during primary leaf infection. On these bases, the aim of my thesis was to characterize the determinism of the concerted effector gene expression. Are AT-isochores targets of reversible epigenetic modifications that affect the regulation of effector genes? and/or are one or several common regulators involved in the control of the concerted expression of effector genes? To assess the role of the structure of AT-isochores, functional analysis of three key players involved in chromatin remodeling (i.e. HP1, DIM-5 and DMM-1) was performed and their role in global gene expression was assessed. This study validated that heterochromatic structure of AT-isochores represses expression of genes located in such a genomic environment, notably effector genes. Among genes under an epigenetic control, we also identified genes located in GC-isochores that were similarly influenced and may represent “hot spots” for epigenetic control. To identify putative regulators of effector gene expression, we established the complete repertoire of transcription factors (TFs) of Lmb and by analyzing the conservation of this repertoire among species of the Leptosphaeria species complex, we identified TFs specific of Lmb, or specifically induced during infection. Functional analysis of 12 TFs was set up: nine TF-encoding genes induced during infection and three orthologs of TFs described as required for pathogenesis in other phytopathogenic fungi (StuA, Sge1, Fox1). This functional analysis showed that StuA, as in other phytopathogenic fungi, plays a major role in infection and expression of effector genes in Lmb. The silencing of an AT-Hook type TF, family of TFs that specifically interact with AT-rich sequences, was associated with a reduction of the expression of two effector genes during infection and with pathogenicity defects. This study brought new insights into the regulation of effector genes in a phytopathogenic fungus involving, for the first time, an epigenetic mechanism
Edmond, Valérie. "Caractérisation de nouvelles fonctions biologiques et modifications post-traductionnelles du facteur d'épissage SC35 dans des modèles cellulaires de carcinomes pulmonaires." Phd thesis, Grenoble, 2010. http://tel.archives-ouvertes.fr/tel-00531801.
Повний текст джерелаLavoie, Sébastien. "Caractérisation de hSpt5 : un facteur de régulation de l'élongation de la transcription." Paris, Muséum national d'histoire naturelle, 2003. http://www.theses.fr/2003MNHN0007.
Повний текст джерелаThe phosphorylation of the largest subunit of RNA polymerase II (Rpb1) is important for the regulation of transcription. We have studied its phosphorylation state in different species after heat shock. MAb CC-3 recognizes Rpb1 in normal condition, its reactivity being reduced following heat shock. The antibody MPM-2 shows an increased reactivity towards Rpb1 after heat shock. Therefore, mAbs CC-3 and MPM-2 are able to discriminate between subsets of Rpb1 which could be functionaly distinct. CC-3 also recognizes a 180-kDa protein which is probably hSpt5, a transcription regulation factor. Rpb1 and hSpt5 are dephosphorylated when cells are exposed to Cdk9 kinase inhibitors, suggesting that it is the major kinase phosphorylating Rpb1 and hSpt5 in vivo. We also demonstrate that the peptidyl-prolyl isomerase Pin1 interacts with phosphorylated hSpt5. The phosphorylation of Rpb1 and hSpt5 followed by Pin1 interaction might thus contribute to the regulation of transcription
Livet, Jean. "Spécification, guidage axonal, migration, survie : le développement de sous-populations de motoneurones chez l'embryon de souris." Aix-Marseille 2, 2001. http://www.theses.fr/2001AIX22072.
Повний текст джерелаQuentien, Marie-Hélène. "Différenciation des cellules du lignage antéhypophysaire somatolactotrope : un r^ole pour les facteurs de transcription Pitx1 et Pitx2." Aix-Marseille 2, 2002. http://www.theses.fr/2002AIX22080.
Повний текст джерелаGross, Klerlein Christian. "Etude de la régulation et du rôle du facteur de complexe ternaire Net en hypoxie." Université Louis Pasteur (Strasbourg) (1971-2008), 2006. http://www.theses.fr/2006STR13136.
Повний текст джерелаHypoxia is defined as a lack of oxygen necessary for the aerobic physiology of the cell. The transcription factor Net (Elk3/Sap-2/Erp) belongs to the ternary complex factors subfamily of the Ets protein. Net is a transcriptional repressor that can be switched to an activator after phosphorylation by the MAP kinases. Net regulates several processes, such as migration, angiogenesis, wound healing and tumorigenesis. Apart from phosphorylation, the pathways regulating Net itself remain to be identified. Interestingly, hypoxia is implicated in all the processes regulated by Net and it induces all its target genes. In hypoxia, Net is polyubiquitylated, exported from the nucleus and degraded by the proteasome. The “prolyl-4-hydroxylases containing-domains” (PHDs), known as the oxygen cellular sensors and inducers of the major factor HIF-1degradationregulate Net. Their inhibition induces a downregulation of Net at the protein level and, conversely, their overexpression delays Net hypoxic degradation. The loss of the transcriptional repressor Net participates in the hypoxic induction of target genes PAI-1, c-fos and egr-1. The phosphorylated form of Net is more stable in hypoxia, which could explain its detection in several tumour types that often have hypoxic regions. Net cooperates with HIF in the hypoxic induction of some genes, but they regulate separately some others. A large scale transcriptional analysis is in progress to estimate their roles. Net mutant mice treated with hypoxia inducer cobalt chloride reveal a potential role of Net in the regulation of the haematocrit. This suggests that Net could play a role in physiological responses in vivo induced in hypoxia. Net downregulation by RNAi inhibits the hypoxic stabilisation of HIF-1 at the protein level. This could be due to an overexpression of PHD 2 and 3 at the transcriptional level as shown by a partial analysis of the microarray results. Thus Net could be a regulator of HIF-1 via the PHDs
Vincent, Audrey. "Régulation des gènes MUCs 11P15 et MUC4 par les mécanismes épigénétiques et par les facteurs de différenciation cellulaire." Lille 2, 2007. http://www.theses.fr/2007LIL2S027.
Повний текст джерелаRobert, Nicholas. "Régulation de l'expression de gènes testiculaires par les facteurs de transcription Gata." Thesis, Université Laval, 2008. http://www.theses.ulaval.ca/2008/25757/25757.pdf.
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