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Fischer, Sabine. "Inducible systems for the characterization of insulating and repressing motifs." kostenfrei, 2009. http://d-nb.info/999863568/34.
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Nobelen, Suzanne van de. "Touched by CTCF analysis of a multi-functional zinc finger protein /." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/12282.
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Panzer, Imke [Verfasser]. "Identifizierung und Analyse von Protein-Interaktionspartnern des Isolationsfaktors CTCF / Imke Panzer." Gießen : Universitätsbibliothek, 2012. http://d-nb.info/1063954177/34.
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Zielke, Katrin [Verfasser], and Andreas [Akademischer Betreuer] Burkovski. "The insulator protein CTCF and cohesins are critical for Herpesvirus saimiri genome maintenance = Das Insulatorprotein CTCF und Kohäsine sind kritisch für die Erhaltung der Genome von Herpesvirus saimiri / Katrin Zielke. Betreuer: Andreas Burkovski." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2012. http://d-nb.info/1021259632/34.
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Segueni, Julie. "DNA methylation changes CTCF binding and reorganizes 3D genome structure in breast cancer cells." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL020.
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Les génomes des mammifères adoptent une organisation 3D fonctionnelle où les interactions entre les enhancers et les promoteurs des gènes sont contenues à l'intérieur de domaines d'association topologique (TADs). La protéine insulatrice CTCF a deux rôles dans ce processus : sa liaison aux promoteurs permettant la formation de boucles enhancers-promoteurs (structure intra-TAD) et sa liaison aux frontières des TADs empêchant la formation de boucles ectopiques entre domaines voisins. Surtout, les perturbations de la liaison de la protéine CTCF à des sites particuliers dans des cellules cancéreuses peuvent être dues à des changements de séquences d'ADN (mutations) ou à des changements de méthylation de l'ADN (épi-mutations). Nous avons d'abord réalisé des expériences calibrées de CTCF ChIP-seq et avons trouvé qu'un grand nombre de sites ont une liaison différente de CTCF, avec une grande fraction de sites différemment liés étant partagés parmi les lignées cancéreuses. Ces changements de liaison de CTCF peuvent être des gains ou des pertes de liaison et sont souvent situés près de gènes associés à la transformation cancéreuse. Nous avons trouvé une remarquable corrélation entre les changements de liaison de CTCF et les changements d'enrichissement de la marque H3K27ac, indiquant un lien entre la liaison de CTCF et l'activité d'éléments cis-régulateurs (CREs). Grâce à des expériences de Hi-C à haute résolution, nous avons évalué l'impact de ces changements de liaison de CTCF sur la structure de la chromatine, caractérisant une réorganisation considérable de la structure 3D du génome à des loci de gènes qui contiennent des pics CTCF perturbés. De manière inattendue, nous trouvons les exemples les plus drastiques de réorganisation à l'intérieur des TADs, au niveau des boucles enhancers-promoteurs. Ensuite, nous avons identifié les changements de méthylation de l'ADN comme la cause de la dérégulation de la liaison de CTCF dans notre modèle. En utilisant un agent retirant la méthylation de l'ADN sur l'ensemble du génome, nous avons réussi à partiellement inverser des changements de liaison de CTCF que nous avons observés et les changements d'expression induits. Ainsi, notre étude identifie une réorganisation invasive de la liaison de CTCF et des structures intra-TADs, induite par la méthylation de l'ADN. Ces épi-mutations récurrentes peuvent expliquer les mécanismes de dérégulation commune des gènes dans les cancersMammalian genomes adopt a functional 3D organization where enhancer-promoter interactions are constrained within Topologically Associating Domains (TADs). The CTCF insulator protein has a dual role in this process, with binding at promoters resulting in the formation of enhancer-promoter loops (intra-TAD structure) and binding at TAD boundaries preventing the formation of inappropriate loops between neighboring domains. Importantly, perturbations of CTCF binding at specific sites in cancer cells can be caused by both changes to the DNA sequence (mutations) or DNA methylation changes (epi-mutations). We first performed precisely-calibrated CTCF ChIP-seq experiments and found that a large number of sites are differentially bound, with a substantial fraction of differential CTCF binding peaks shared among cancer cell lines. Differential CTCF peaks can both be gained and lost and are often localized close to genes associated with breast cancer transformation. We found a striking correlation between CTCF binding changes and H3K27ac changes indicating a link between CTCF binding and the activity of cis-regulatory elements (CREs). Using high-resolution Hi-C, we assessed the impact of differential CTCF binding on chromatin structure, characterizing considerable 3D genome reorganization at gene loci with perturbed CTCF peaks. Unexpectedly, we find the most drastic examples of reorganization within TADs, at the level of enhancer-promoter loops. Then, we identified DNA methylation changes as the upstream cause of CTCF binding deregulation in our breast cancer model. Using genome-wide hypomethylating agent, we were able to partially reverse observed CTCF binding changes and the gene expression changes they induced. Our work thus identifies a pervasive DNA-methylation-guided reorganization of CTCF binding and intra-TAD structure. Such recurrent patterns of epi-mutations can provide a mechanistic explanation for shared gene deregulation in cancers
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Malashchuk, Ogor. "Epigenetic regulation of skin development and postnatal homeostasis : the role of chromatin architectural protein Ctcf in the control of keratinocyte differentiation and epidermal barrier formation." Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/14791.
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Epigenetic regulatory mechanisms play important roles in the control of lineage-specific differentiation during development. However, mechanisms that regulate higher-order chromatin remodelling and transcription of keratinocyte-specific genes that are clustered in the genome into three distinct loci (Keratin type I/II loci and Epidermal Differentiation Complex (EDC)) during differentiation of the epidermis are poorly understood. By using 3D-Fluorescent In Situ Hybridization (FISH), we determined that in the epidermal keratinocytes, the KtyII and EDC loci are located closely to each other in the nuclear compartment enriched by the nuclear speckles. However, in KtyII locus knockout mice, EDC locus moved away from the KtyII locus flanking regions and nuclear speckles towards the nuclear periphery, which is associated with marked changes in gene expression described previously. Chromatin architectural protein Ctcf has previously been implicated in the control of long-range enhancer-promoter contacts and inter-chromosomal interactions. Ctcf is broadly expressed in the skin including epidermal keratinocytes and hair follicles. Conditional Keratin 14-driven Ctcf ablation in mice results in the increase of the epidermal thickness, proliferation, alterations of the epidermal barrier and the development of epidermal pro-inflammatory response. Epidermal barrier defects in Krt14CreER/Ctcf fl/fl mice are associated with marked changes in gene expression in the EDC and KtyII loci, which become topologically segregated in the nucleus upon Ctcf ablation. Therefore, these data suggest that Ctcf serves as critical determinant regulating higher-order chromatin organization in lineage-specific gene loci in epidermal keratinocytes, which is required for the proper control of gene expression, maintenance of the epidermal barrier and its function.
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Malashchuk, Igor. "Epigenetic Regulation of Skin Development and Postnatal Homeostasis The role of chromatin architectural protein Ctcf in the control of Keratinocyte Differentiation and Epidermal Barrier Formation." Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/14791.
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Epigenetic regulatory mechanisms play important roles in the control of lineage-specific differentiation during development. However, mechanisms that regulate higher-order chromatin remodelling and transcription of keratinocyte-specific genes that are clustered in the genome into three distinct loci (Keratin type I/II loci and Epidermal Differentiation Complex (EDC) during differentiation of the epidermis are poorly understood. By using 3D-Fluorescent In Situ Hybridization (FISH), we determined that in the epidermal keratinocytes, the KtyII and EDC loci are located closely to each other in the nuclear compartment enriched by the nuclear speckles. However, in KtyII locus knockout mice, EDC locus moved away from the KtyII locus flanking regions and nuclear speckles towards the nuclear periphery, which is associated with marked changes in gene expression described previously. Chromatin architectural protein Ctcf has previously been implicated in the control of long-range enhancer-promoter contacts and inter-chromosomal interactions. Ctcf is broadly expressed in the skin including epidermal keratinocytes and hair follicles. Conditional Keratin 14-driven Ctcf ablation in mice results in the increase of the epidermal thickness, proliferation, alterations of the epidermal barrier and the development of epidermal pro-inflammatory response. Epidermal barrier defects in Krt14CreER/Ctcf fl/fl mice are associated with marked changes in gene expression in the EDC and KtyII loci, which become topologically segregated in the nucleus upon Ctcf ablation. Therefore, these data suggest that Ctcf serves as critical determinant regulating higher-order chromatin organization in lineage-specific gene loci in epidermal keratinocytes, which is required for the proper control of gene expression, maintenance of the epidermal barrier and its function.
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Shamsuddin, S. "Biochemical characterization of the interactions between a transcription factor, CTCF and its partners Y-Box binding protein-1, and the large subunit of RNA polymerase II." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269484.
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Alharbi, Adel Braik M. "Characterising the Roles of Zinc Finger Proteins CTCF and ZRANB2 in Modulating Alternative Splicing." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/27996.
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Zinc finger (ZF) proteins constitute the most abundant protein class and are involved in multiple biological processes including development, differentiation, tumour suppression and apoptosis. CTCF and ZRANB2 are two ZF proteins that have been recently linked to modulation of alternative splicing (AS). AS is a complex biological process enriching transcriptome and proteome diversity by facilitating the production of multiple mRNA and protein isoforms from individual genes. However, the genome-wide impact of Ctcf and Zranb2 dosage on AS has not been investigated.
The present study examined the effect of Ctcf haploinsufficiency and Zranb2 deficiency on gene expression and AS in Ctcf hemizygous (Ctcf+/-) and conditional Zranb2 knockout (Zranb2-/-) mice, respectively. Reduced Ctcf and Zranb2 levels caused distinct differences in gene expression and AS. In Ctcf+/- mice, these differences were tissue-specific and exhibited a significant increase in intron retention in Ctcf+/- liver and kidney. Interestingly, Ctcf binding sites were enriched proximal to the genomic regions of the intron-retaining genes in Ctcf+/- liver.
Proteomic analysis of Ctcf interacting partners in five mouse tissues identified the Small RNA Binding Exonuclease Protection Factor La (Ssb) as a novel Ctcf interactor in all the examined tissues. Tissue-specific protein interactions with Ctcf were also observed. In the brain, co-immunoprecipitation was used to experimentally validate Ctcf interactions with Tra2β, C1qbp, Cpsf6 as well as Atxn1, which are known to be involved in pre-mRNA splicing and brain development, respectively.
This study provides new insights into effects of Ctcf haploinsufficiency and Zranb2 deficiency on the transcriptome and highlights a new role for Ctcf in mediating tissue-specific intron retention and protein interactions.
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Ball, DeAnna K. "Establishment of a recombinant CTGF expression system in vitro that models CTGF processing in vivo : structural and functional characterization of multiple mass CTGF proteins /." The Ohio State University, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486397841221133.
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Pi, Liya. "The role of connective tissue growth factor (ctgf) in oval cell aided liver regeneration in the 2-aaf/phx model." [Gainesville, Fla.] : University of Florida, 2005. http://purl.fcla.edu/fcla/etd/UFE0010022.
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Thesis (Ph.D.)--University of Florida, 2005.Typescript. Title from title page of source document. Document formatted into pages; contains 162 pages. Includes Vita. Includes bibliographical references.
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Koga, Kenichi. "MicroRNA-26a inhibits TGF-β-induced extracellular matrix protein expression in podocytes by targeting CTGF and is downregulated in diabetic nephropathy." Kyoto University, 2016. http://hdl.handle.net/2433/204573.
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Panek, Anna [Verfasser]. "Rolle des Connective Tissue Growth Factors (CTGF) und des PKC-enhanced Protein-Phosphatase 1 Inhibitors (KEPI) für die Funktion des adulten Herzen : Studien an transgenen Tiermodellen / Anna Naila Panek." Berlin : Freie Universität Berlin, 2008. http://d-nb.info/1023375095/34.
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Breuninger, Stephanie [Verfasser], Gabriele [Akademischer Betreuer] Multhoff, Gabriele [Gutachter] Multhoff, and Thomas E. [Gutachter] Schmid. "Utilizing Heat Shock Protein 70 (Hsp70) as a Tumor-Specific Blood Biomarker and for the Isolation of Circulating Tumor Cells (CTCs) / Stephanie Breuninger ; Gutachter: Gabriele Multhoff, Thomas E. Schmid ; Betreuer: Gabriele Multhoff." München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1187917079/34.
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Laurent, Anouchka. "Caracterisation et modélisation des pathologies lymphoides présentant des gains du chromosome 21." Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7061.
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Les gains somatiques du chromosome 21 (+21) sont fréquemment observés dans les hémopathies, et les enfants atteints par le Syndrome de Down (DS, trisomie 21 constitutive) ont un risque plus élevé de développer des leucémies durant l’enfance. Ces observations indiquent que +21 participent au développement leucémique. Cependant, la trisomie 21 seule n’est pas suffisante. L'objectif de cette thèse a été de caractériser et modéliser les altérations génétiques coopérant avec les gains du chromosome 21. Un premier axe a permis d’étudier l’impact de la mutation activatrice JAK3A572V dans un modèle murin (knock-in au locus endogène) dans le développement d’un lymphome cutané à cellules T (CTCL). Croisé avec un modèle de trisomie 21 partiel (Ts1Rhr), la latence de ce CTCL est fortement réduite, indiquant une coopération oncogénique. Dans un deuxième axe, j'ai identifié une forte incidence des altérations activant de la voie RAS/MAPK dans les leucémies aiguës lymphoblastiques B pédiatriques (LAL-B) +21. J'ai démontré que la mutation KRASG12D coopère fonctionnellement avec la trisomie 21 dans le processus de transformation à la fois dans des modèles cellulaires murins et des cellules leucémiques humaines. J’ai également développé 20 modèles de xénogreffes pour tester l’efficacité du trametinib, un inhibiteur de la voie RAS/MAPK. Seul ou en combinaison avec des chimiothérapies conventionnelles (vincristine), j’ai montré que l’inhibition de la voie RAS/MAPK prolonge la survie de ces souris. Ces données indiquent que la caractérisation et le ciblage d’événements de coopération permettent de proposer de nouvelles stratégies thérapeutiques pour les leucémies pédiatriques avec +21Somatic gains of chromosome 21 (+21) are hallmark of hematological malignancies, and children with Down Syndrome (DS, constitutive trisomy 21) are predisposed to develop leukemia. These observations strongly suggest that gains of chromosome 21 promote leukemia development; however, alone, it is not sufficient. The aim of my PhD work was to identify and functionally characterize the genetic alterations cooperating with +21. My first aim was focused on studying the impact of the JAK3A572V activating mutation in the development of cutaneous T cell lymphoma (CTCL), using a new knock-in model carrying this alteration at the endogenous locus. In this study, I showed that partial trisomy 21 (Ts1Rhr) cooperates with the JAK3A572V mutation to reduce the latency of this pathology, thus highlighting a mechanism of oncogenic cooperation. In a second aim, I identified a high incidence of genetic alterations leading to RAS/MAPK pathway activation in B cell leukemia samples carrying +21 (B-ALL+21). I have demonstrated that the KRASG12D mutation functionally cooperates with trisomy 21 in transformation process of both murine and human cellular models. In order to test new molecules to improve the treatment of LAL-B+21, I have also developed 20 xenograft models. Treatment of these models with trametinib, a RAS/MAPK pathway inhibitor, alone or in combination with conventional chemotherapies (vincristine), improve their survival. Together, these data indicate that characterizing and targeting cooperation events allow to propose novel therapeutic strategies in pediatric leukaemia with +21
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Tulukcuoglu, Güneri Ezgi. "Development of microfluidic device for high content analysis of circulating tumor cells." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066583/document.
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Le cancer est l'une des principales causes de décès dans le monde. D'après la société américaine contre le cancer; en 2015, un quart des décès aux Etats-Unis est du au cancer du poumon avant même les maladies cardiaques. Cette situation nous incite et bien d'autres scientifiques dans le monde à développer des moyens plus efficaces de traitement, le diagnostic et le dépistage de la maladie. Parce que près de 90% des décès par cancer sont dus à des métastases, de nombreuses études se sont concentrées sur le mécanisme de métastases et sur son impact clinique. Les cellules tumorales circulantes (CTC) sont les cellules s’échappent de tumeurs primaires ou métastatiques pour rejoindre le flux sanguin périphérique, ces cellules sont un élément de transition dans le processus métastatique et portent ainsi des informations cruciales sur ce mécanisme encore mal compris. Les CTCs ont déjà montré leur potentiel comme biomarqueur de pronostic de la progression de la maladie et de l'indicateur de l'efficacité du traitement en fonction l’augmentation ou de la diminution de leur nombre. Leur caractérisation moléculaire peut également donner des informations vis à vis de cibles thérapeutiques possibles et des mécanismes de progression de la maladie ou de la résistance aux médicaments. Leur comptage au cours du traitement combiné avec leur caractérisation moléculaire devrait améliorer la prise en charge des patients dans le cadre de la médecine personnalisée. Cependant CTCs sont extrêmement rares, 1 à 10 cellules / ml de sang parmi les 106 globules blancs et 109 globules rouges, leur capture à partir du sang reste donc un challenge analytique. Dans les dernières décennies, Une grande variété de techniques d'enrichissement et de capture a été mise au point et l'approche microfluidique est l'une des méthodes efficaces, flexibles et à haut débit. Au sein de notre équipe, un dispositif microfluidique (système Ephesia) puissant pour la capture et l'analyse des cellules tumorales circulantes a déjà été mis au point précédemment. Le principe de capture est basé sur l'auto-assemblage de billes magnétiques greffées par des anticorps, grâce aux quelles les cellules sont enrichies via l’interaction Ab- l'antigène de surface EpCAM que l'on trouve communément dans les cellules cancéreuses d'origine épithéliale. Ce système a déjà été validé avec des lignées cellulaires et des échantillons de patients. Cependant, le système n'a pas permis l'isolement / détection des sous-populations de CTCs ou d'effectuer une caractérisation moléculaire très poussée. Par conséquent, mon projet de thèse vise à améliorer encore les capacités du système sur les deux principaux aspects: le ciblage sous-populations de CTC et à l'étude des interactions des protéines à la surface des CTCs dans le Système EphesiaMetastasis is the advanced stage of cancer progression and is the cause of 90% of deaths in cancer disease. During metastatic cascade, it is suggested that the successful metastatic initiation depends on the survival of circulating tumor cells (CTCs). CTCs are the cells that shed from the primary or secondary tumor sites into the blood circulation. it is now widely recognized as potential biomarker for companion diagnostics in which high number of CTCs in blood can indicate association with poor survival or high risk of disease progression. Besides, following the number of CTCs during the course of treatment can help to adapt the selected therapy and predict the treatment efficacy. On the other hand molecular characterization can provide patient stratification and identifying the therapeutic targets. However they are extremely rare in the bloodstream, estimated between 1-10 CTC among 6×106 leukocytes, 2×108 platelets and 4×109 erythrocytes per one mL of blood which makes their isolation very challenging. A very attractive way of isolation of CTCs is to integrate microfluidics. Microfluidics offers great advantages such as low volume of reagent consumption and short analysis times with automation as well as isolation and detection analysis can be integrated resulting in highly efficient biomedical devices for diagnostics. As parallel to state of the art, a powerful microfluidic device for circulating tumor cells capture and analysis had already been developed previously in our laboratory. The principle of capture is based on self-assembly of antibody-coated (EpCAM) magnetic beads in which the cells are enriched by EpCAM surface antigen which is found commonly in epithelial origin cancer cells. This system was already validated with cell lines and patients samples. However, the system did not allow isolation/detection of subpopulations of CTCs or performing high content molecular characterization. Therefore, my PhD project aimed at further improving the capabilities of the system on the main two aspects: targeting subpopulations of CTC and studying of protein interactions of CTCs in Ephesia System
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LOCATELLI, LUIGI. "Expression of aVB6 integrin by Pkhd1-defective cholangiocytes links enhanced ductal secretion of Macrophage chemokines to progressive portal fibrosis in Congenital Hepatic Fibrosis." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/41733.
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BACKGROUND AND AIMS: Congenital Hepatic Fibrosis (CHF) is caused by mutations in PKHD1, a gene encoding for fibrocystin, a protein of unknown function, expressed in cholangiocyte cilia and centromers. In CHF, biliary dysgenesis is accompanied by severe progressive portal fibrosis and portal hypertension. The mechanisms responsible for portal fibrosis in CHF are unclear. The αvβ6 integrin mediates local activation of TGFβ1 and is expressed by reactive cholangiocytes during cholestasis. To understand the mechanisms of fibrosis in CHF we studied the expression of αvβ6 integrin and its regulation in Pkhd1del4/del4 mice.
METHODS: In Pkhd1del4/del4 mice we studied, at different ages (1-12 months): a) portal fibrosis (Sirius Red) and portal hypertension (spleen weight/body weight); b) αvβ6 mRNA and protein expression (RT-PCR, IHC); c) α-SMA and TGFβ1 mRNA expression (RT-PCR); d) portal inflammatory infiltrate (IHC for CD45 and FACS analysis of whole liver infiltrate); f) cytokines secretion from cultured monolayers of primary cholangiocytes (Luminex assay); g) cytokine effects on monocyte/macrophage proliferation (MTS assay) and migration (Boyden chamber); h) TGFβ1 and TNFα effects on β6 integrin mRNA expression by cultured cholangiocytes before and after inhibition of the TGFβ receptor type II (TGFβRII); i) TGFβ1 effects on collagen type I (COLL1) mRNA expression by cultured cholangiocytes.
RESULTS: Pkhd1del4/del4 mice showed a progressive increase in αvβ6 integrin expression on biliary cyst epithelia. Expression of αvβ6 correlated with portal fibrosis (r=0.94, p<0.02) and with enrichment of a CD45+ve cell infiltrate in the portal space (r=0.97, p<0.01). Gene expression of TGFβ1 showed a similar age-dependent increase. FACS analysis showed that 50-75% of the CD45+ve cells were macrophages (CD45/CD11b/F4/80+ve). Cultured polarized Pkhd1del4/del4 cholangiocytes secreted from the basolateral side significantly increased amounts of CXCL1 and CXCL10 (p<0.05). Both cytokines were able to stimulate macrophage migration (p<0.05). Basal expression of β6 mRNA by cultured Pkhd1del4/del4 cholangiocytes (0.015±0.002 2^-dCt) was potently stimulated by the macrophage-derived cytokines TGFβ1 (0.017±0.002 2^-dCt, p<0.05) and TNFα (0.018±0.003 2^-dCt, p<0.05). Inhibition of TGFβRII completely blunted TGFβ1 (0.014±0.003 2^-dCt, p<0.05) but not TNFα effects (0.017±0.001 2^-dCt, p=ns) on β6 mRNA. COLL1 mRNA expression by cultured Pkhd1del4/del4 cholangiocytes (0.0009±0.0003 2^-dCt) was further and significantly increased after TGFβ1 stimulation (0.002±0.0005 2^-dCt, p<0.05).
CONCLUSIONS: Pkhd1del4/del4 cholangiocytes possess increased basolateral secretory functions of chemokines (CXCL1, CXCL10) able to orchestrate macrophage homing to the peribiliary microenvironment. In turn, by releasing TGFβ1 and TNFα, macrophages up-regulate αvβ6 integrin in Pkhd1del4/del4 cholangiocytes. αvβ6 integrin activates latent TGFβ1, further increasing the fibrogenic properties of cholangiocytes.
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MacPherson, Melissa. "Biochemical Studies of the CTCF Insulator Protein: Determination of Protein Interactions with CTCF using Tandem Affinity Purification, Characterization of its Post-translational Modification by the Small Ubiquitin-like Modifier Proteins and Studies of CTCF DNA Looping Ability." Thesis, 2010. http://hdl.handle.net/1807/26205.
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The CTCF protein is involved in several important aspects of gene regulation including transcriptional activation, transcriptional repression and insulator ability. It is also involved in the regulation of epigenetic processes including X-chromosome inactivation and the maintenance of genomic imprinting. CTCF has been shown to bind to approximately 15 000 sites in the mammalian genome and has been implicated in nuclear organization. The CTCF protein mediates long-range chromatin interactions and is believed to form DNA loops. It also acts to block the communication of an enhancer with a promoter by acting as an insulator. Despite its importance in gene regulation, the molecular mechanisms that govern CTCF’s ability to perform its myriad functions remain enigmatic.
In this thesis, I add insight into our understanding of the mechanisms behind CTCF’s function. I show that CTCF is post-translationally modified by the Small Ubiquitin-like Modifier proteins and that this post-translational modification contributes to its repressive ability at the c-myc P2 promoter. I also show that CTCF is localized to the sub-nuclear compartment called the Polycomb bodies. The Polycomb protein Pc2 acts as an E3 ligase to enhance the SUMOylation of CTCF by SUMOs 2 and 3. These findings help to explain CTCF’s ability to act as a transcriptional repressor.
I also report biochemical evidence to support the role for CTCF in forming an unusual DNA structure, possibly a loop. I hypothesize that a single CTCF binding site is able to form DNA loops. These findings suggest mechanisms by which CTCF is able to organize the mammalian genome and to function as an insulator protein. In addition to these findings I have also purified CTCF interacting proteins through the use of the tandem affinity purification technique. The interacting proteins contain many chromatin and DNA binding proteins further suggesting a role for CTCF in chromatin organization. The results in this thesis enhance our knowledge of the molecular mechanisms of CTCF function and provide a basis for the improved understanding of CTCF mediated gene expression.
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Johanson, Michael. "An Investigation of Insulator Proteins in Mosquito Genomes." Thesis, 2013. http://hdl.handle.net/1969.1/151362.
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Transgenic mosquitoes are beneficial for the design and implementation of various pathogen control programs. However, low and variable expression of transgenes caused by position effects is a hindrance to the characterization and effective use of transgenes in mosquito species. The use of insulator sequences to flank transgenes may have the ability to overcome position effects caused by the genomic environment surrounding the insertion site. CTCF is a multifunctional protein, conserved from humans to Drosophila. Its role as an enhancer blocker in the Drosophila bithorax complex and its proximal binding to other insulator proteins on Drosophila chromosomes makes it a good candidate for identifying insulator sequences throughout the mosquito genome that may be used to improve mosquito transgenesis. Its multi-functionality as a transcription factor and genome organizer also makes CTCF worthy of investigation for an improved understanding of the regulation of the mosquito genome. This study uses chromatin immunoprecipitation with an An. gambiae CTCF antibody followed by Illumina deep sequencing (ChIP-Seq) to identify regions of CTCF binding throughout the An. gambiae genome. A subset of the CTCF binding site peaks was validated using ChIP-PCR. Another subset of this data set, including the ChIP-PCR validated peaks, was input into the motif finding tool, AlignACE, in order to identify a CTCF binding site consensus. Four motifs were identified, none of which were found in more than 11.9% of the ChIP-Seq data set. These results lead us to conclude that An. gambiae CTCF binds to a wider variety of sequences compared to Drosophila CTCF. This work also includes a comparison of the expression profiles of the dipteran insulator proteins, Su(Hw) and CP190, with that of CTCF across multiple life stages in Ae. aegypti. The results of this study suggest the possibility of genomic colocalization, as has been recently discovered in Drosophila. The identification of CTCF binding site peaks throughout the An. gambiae genome provides a large data set of potential insulator sequences that may be used to improve mosquito transgenesis, and provide a new model for the study of CTCF function in a species with medical significance.
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"Functional characterization of CCCTC-binding factor (CTCF) in the pathogenesis of hepatocellular carcinoma." 2013. http://library.cuhk.edu.hk/record=b5884412.
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Zhang, Bin.Thesis (Ph.D.)--Chinese University of Hong Kong, 2013.
Includes bibliographical references (leaves 154-187).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.
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Chien, Chia-Hung, and 簡嘉宏. "Functional Analysis of Zebrafish CTGF gene promoter by Transgenic Assay with Green Fluorescent Protein (GFP) Reporter Gene." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/30067652716686339852.
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碩士臺灣大學
口腔生物科學研究所
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Connective tissue growth factor (CTGF), a member of CCN family, is a cysteine-rich, secreted, extracellular matrix-associated protein that regulates diverse cellular functions in different cell types. It modulates many cellular functions, including cell proliferation, migration, adhesion, and extracellular matrix production. Evidence suggests that there is a distinctive function of CTGF in the skeletal development. For instance, during Meckel''s cartilage development, CTGF acts as a down-stream molecule of TGF-β to stimulate cell-cell interactions and the expression of condensation-associated genes. Actually, TGF-β response element is located on the CTGF gene, and CTGF can exert many functions by the induction of TGF-β. The aim of this study was to analyze the zebrafish CTGF promoter. Its cognate genomic DNA fragments were amplified by polymerase chain reaction (PCR). Upstream promoter (enhancer) fragments were constructed with EGFP (enhanced green fluorescent protein) reporter gene or with HSV-tymidine kinase (TK) basal promoter and analyzed in vivo by transient transgenic assays using zebrafish embryos. Results demonstrate that the constructs of pZF-CTGF(-2893/ +105)-EGFP1 [pCTGF- EGFP1] and pZF-CTGF(-1593/-1462)-HSV-TK-EGFP1 [pCTGF-E2-TK EGFP1]can drive the specific expression of GFP in zebrafish embryo(5dpf). The expression sites include mandible, cranium, cornea, heart, somite, notochord, floor plate, fin bud, and epidermis. It is identical to in situ hybridization result. Furthermore,the proximal promoter constructs of the pZF-CTGF(-195/+22)-EGFP1 [pCTGF-P200- EGFP1], pZF-CTGF(-64/+22)-EGFP1 [pCTGF-vTATA-EGFP1] and pZF-CTGF(-195/-44)- HSV-TK-EGFP1 [pCTGF-195xTATA-TK-EGFP1] can also drive expression of GFP in zebrafish embryo(5dpf). The expression sites include notochord and somite. However, the expression area is fewer. The zebrafish transgenic stable lines were not obtained from pZF-CTGF(-2893/+105)-EGFP1 [pCTGF-EGFP1] construct yet. The results suggest that the tissue-specific regulatory elements of the zebrafish CTGF reside within the upstream conserved region (-1593/-1462) and proximal promoter region (-195/ +22), and the regulatory mechanism of CTGF may be conserved among the vertebrate species.
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Singh, Simranjit. "Redox regulation of protein phosphatase-1 and ER stress regulation of connective tissue growth factor in cardiomyocytes." Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-0023-3E92-5.
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Kittana, Naim. "Role of Secretory Processes in Cardiac Fibroblasts for Heart Failure Development and Progression." Doctoral thesis, 2014. http://hdl.handle.net/11858/00-1735-0000-0023-9947-D.
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