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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

TFAP2A in the neural crest gene regulatory network and disease

Hallberg, Andrea Rachel 01 May 2019 (has links)
The neural crest is a transient, multipotent, cell population that gives rise to several important tissues during embryonic development, including the craniofacial skeleton, peripheral nervous system, and melanocytes. The neural crest arises from the ectoderm, along with the skin and central nervous system. This process of specification is dependent on a gene regulatory network (GRN) which is made up of transcription factors that regulate each other. While we know many of the members of this GRN, the direct connections among the members are largely unsolved. Breakdown of this GRN can lead to birth defects, such as cleft lip and palate, and cancer of neural crest derivatives, such as melanoma, thus understanding the intricate details of this network is important. The transcription factor Tfap2a is an important member of the GRN, as loss of tfap2a and its paralog tfap2c leads to loss of pre-migratory neural crest and all neural crest derivatives. Despite its importance in this network little is known about how its expression is regulated. We hypothesized that, due to its importance in this network, it will have multiple enhancers that drive its expression in the neural crest. We have identified two neural crest enhancers of tfap2a. We found that one of these enhancers is responsive to WNT signals and is maintained by forming a positive feedback loop with Sox10. Our results suggest that this enhancer is important for both induction and maintenance of tfap2a expression in the neural crest. Tfap2 paralogs are important at several different stages throughout neural crest lineage specification. However, the only direct target of Tfap2a that has been identified is sox10. Thus, we wanted to determine the direct targets of Tfap2 in this network. Through the integration of several data sets, including ATAC-seq and expression profiling of tfap2a/c double mutants, we have identified several direct targets including sox9b and alx1. Melanoma is cancer of the melanocytes, a neural crest derivative. Recent studies have shown that melanoma and the neural crest share genetic similarities. TFAP2A expression is decreased in metastatic melanoma compared to primary tumors, thus we wanted to investigate the mechanism of TFAP2A in metastatic melanoma. We found that the promoter of TFAP2A is hypermethylated in some metastatic melanoma tumors. This was confirmed by samples in the TCGA database. Hypermethylation of the promoter contributes to the downregulation of TFAP2A in metastatic melanoma. In conclusion, we have further illuminated the connections among transcription factors in the GRN important for neural crest lineage specification. Further, we have identified a new mechanism regulating TFAP2A expression in metastatic melanoma. Together, these studies reveal regulatory mechanisms of TFAP2A gene expression.
2

REGULATION OF NEURAL CREST DEVELOPMENT REQUIRES FUNCTIONAL INTERACTIONS BETWEEN HDAC1, TFAP2A AND FOXD3

Unal Eroglu, Arife 20 May 2013 (has links)
No description available.
3

Molecular functions of the transcriptional regulator AP-2 alpha (TFAP2A) in the renal collecting duct

Leiz, Janna 26 June 2023 (has links)
Tfap2a gehört zur Familie der AP-2-Transkriptionsfaktoren. Heterozygote Mutationen von TFAP2A im Menschen führen zum Branchio-Okulo-Fazialen-Syndrom (BOFS) und sind mit Nierenanomalien assoziiert. Molekulare Mechanismen, die zu diesen BOFS-assoziierten Nierenanomalien führen, sind noch unbekannt. In diesem Projekt wurde die Expression von Mitgliedern der AP-2-Familie in neugeborenen und erwachsenen Wildtyp-Mäusen analysiert. Tfap2a wurde in der Ureterknospe und der distalen Region des S-förmigen Körpers in den Nieren neugeborener Mäuse exprimiert. Die Expression blieb in ausgereiften distalen Tubuli und Sammelrohren erhalten. Tfap2b, ein zweites Mitglied der AP-2-Familie, das in der Niere exprimiert wird und mit Zystenbildung assoziiert ist, wurde im aufsteigenden Ast der Henleschen Schleife sowie in den distalen Tubuli und dem in der Nierenrinde liegenden Sammelrohr exprimiert. Um die Rolle von Tfap2a in der Niere zu untersuchen, wurden Mäuse mit einer sammelrohrspezifischen Deletion von Tfap2a (Tfap2a-KO) erzeugt. Phänotypische und morphologische Analysen ergaben, dass Tfap2a-KO-Mäuse mäßig reduzierte Nierengewichte und eine fortschreitende Dilatation der äußeren medullären Sammelrohre aufwiesen. Einzelkern- und RNA-Sequenzierung der Nieren adulter Mäuse zeigte eine deregulierte Expression von Genen, die mit der Organisation von Aktinfilamenten, Zelladhäsion, Wnt-Signalen und anderen Signalwegen der Nierenentwicklung in Verbindung stehen. In einem isolierten Modell von kultivierten Sammelrohrzellen mit einer Deletion von Tfap2a waren ähnliche Signalwege dereguliert. Insgesamt deutet diese Studie darauf hin, dass Tfap2a für die Differenzierung des Sammelrohrepithels und die Regulierung des Durchmessers des Tubuluslumens erforderlich ist. Dies ermöglicht Einblicke in die molekularen Grundlagen der beim BOFS beobachteten Nierenfehlbildungen. / The transcriptional regulator Tfap2a is part of the AP-2 transcription factor family. Heterozygous mutations of TFAP2A in humans lead to branchio-oculo-facial syndrome (BOFS) and are associated with renal anomalies. Molecular mechanisms leading to BOFS-associated renal anomalies are still unknown. In this project, expression patterns of AP-2 family members were analyzed in newborn and adult wildtype mice. Tfap2a was expressed in the ureteric bud and distal region of the S-shaped body in kidneys of newborn mice. Expression was maintained in mature distal tubules and collecting ducts. Tfap2b, a second AP-2 family member expressed in the kidney and associated with cyst formation, was found in the ascending limb and showed overlapping expression with Tfap2a in distal tubules and the cortical collecting duct. To investigate the role of Tfap2a in the kidney, mice with a collecting duct-specific deletion of Tfap2a (Tfap2a-KO) were generated by crossing mice carrying a Cre-recombinase under the Hoxb7 promotor and mice with floxed Tfap2a alleles. Phenotypic and morphological analyses revealed that Tfap2a-KO mice displayed moderately reduced kidney weights and a progressive dilation of outer medullary collecting ducts. Single-nucleus and bulk RNA sequencing of kidneys of three months old Tfap2a-KO mice and littermate controls indicated deregulated expression of genes associated with actin filament organization, cell adhesion, Wnt signaling, and other kidney developmental pathways. Genes deregulated in Tfap2a-deficient mice included several genes previously implicated in the development of congenital anomalies of the kidney and urinary tract. In an isolated model of cultured collecting duct cells carrying a Tfap2a knockout similar pathways were deregulated. Taking together, this study indicates that Tfap2a is required for collecting duct epithelium differentiation and tubular lumen diameter regulation, providing insights into the molecular basis of renal defects observed in BOFS.
4

Characterization of HIPSTR highlights the heterogeneous expression pattern of lncRNAs in human embryos and stable cell lines / Caracterização do HIPSTR destaca o padrão de expressão heterogênea de IncRNAs em embriões humanos e linhagens estáveis de células

Yunusov, Dinar 10 June 2016 (has links)
There is a growing appreciation that eukaryotic genomes are transcribed into numerous, previously undetected - and thus uncharacterized regulatory long non-coding RNAs (lncRNAs). Recent studies are primarily focused on lncRNAs transcribed from intergenic regions and enhancers, leaving antisense lncRNAs the least studied group of lncRNAs. At the same time, antisense transcription occurs in up to 74 % of human gene loci, frequently - from the opposite strand of genes encoding proteins involved in regulation of transcription. Here, we identified HIPSTAR (Heterogeneously expressed from the Intronic Plus Strand of the TFAP2A-locus RNA), a novel conserved lncRNA that is transcribed antisense to the TFAP2A gene. Unlike previously reported antisense lncRNAs, HIPSTR expression does not correlate with the expression of its antisense counterpart. Although HIPSTAR and TFAP2A are co-expressed in in vitro derived neural crest and trophoblast cells, only HIPSTAR and not TFAP2A is specifically expressed in a subset of cells within 8-cell- and morula-stage human embryos. We show that, similar to HIPSTAR, in the individual cells of developing human embryos or of stable cell lines the expression of lncRNAs is more highly heterogeneous than the expression of mRNAs. Finally, we demonstrate that HIPSTAR depletion in HEK293 and H1BP, a human embryonic stem cell line, predominantly affects the expression levels of genes involved in early organismal development and cell differentiation. Together, we show that expression of HIPSTAR and hundreds other lncRNAs is highly heterogeneous in human embryos and cell lines. We use HIPSTAR to exemplify the functional relevance of lncRNAs with heterogeneous and developmental stage-specific expression patterns. / Tem sido cada vez mais reconhecido que a transcrição dos genomas eucarióticos produz múltiplos transcritos novos, anteriormente não detectados e ainda não caracterizados, sendo que a maioria é constituida de RNAs não-codificantes longos (lncRNAs) regulatórios. Estudos recentes estão focados principalmente nos lncRNAs transcritos de regiões intergênicas e enhancers; assim, o grupo dos lncRNAs antisenso permanece o menos estudado de todos. Ao mesmo tempo, a transcrição antisenso ocorre em até 74% dos loci de genes humanos, frequentemente - a partir da fita oposta de genes que codificam proteínas envolvidas na regulação da transcrição. No presente trabalho, nós identificamos HIPSTR (Heterogeneously expressed from the Intronic Plus Strand of the TFAP2A-locus RNA), um lncRNA novo conservado que é transcrito a partir da fita antisenso do gene TFAP2A. Ao contrário do anteriormente relatado para os lncRNAs antisenso, a expressão de HIPSTR não está correlacionada com a expressão do gene da fita oposta. HIPSTR e TFAP2A são co-expressos em células da crista neural e em trofoblastos derivadas in vitro, mas somente HIPSTR e não TFAP2A está especificamente expresso num subconjunto de células de embriões humanos nos estágios de 8-células e mórula. Mostramos que, semelhante a HIPSTR, a expressão de lncRNAs é mais altamente heterogênea que a expressão de mRNAs em células individuais de embriões humanos em desenvolvimento ou em linhagens estáveis de células. Finalmente, nós demonstramos que a depleção de HIPSTAR em células HEK293 e H1BP, uma linhagem de células tronco embrionárias humanas, afeta predominantemente os níveis de genes envolvidos no início do desenvolvimento do organismo e na diferenciação de células. No conjunto, nós mostramos que a expressão de HIPSTR e de centenas de outros lncRNAs é altamente heterogênea em embriões humanos e linhagens celulares. Usamos HIPSTR para exemplificar a relevância funcional de lncRNAs com padrões de expressão heterogêneos e estágio-de-desenvolvimento específicos.
5

Characterization of HIPSTR highlights the heterogeneous expression pattern of lncRNAs in human embryos and stable cell lines / Caracterização do HIPSTR destaca o padrão de expressão heterogênea de IncRNAs em embriões humanos e linhagens estáveis de células

Dinar Yunusov 10 June 2016 (has links)
There is a growing appreciation that eukaryotic genomes are transcribed into numerous, previously undetected - and thus uncharacterized regulatory long non-coding RNAs (lncRNAs). Recent studies are primarily focused on lncRNAs transcribed from intergenic regions and enhancers, leaving antisense lncRNAs the least studied group of lncRNAs. At the same time, antisense transcription occurs in up to 74 % of human gene loci, frequently - from the opposite strand of genes encoding proteins involved in regulation of transcription. Here, we identified HIPSTAR (Heterogeneously expressed from the Intronic Plus Strand of the TFAP2A-locus RNA), a novel conserved lncRNA that is transcribed antisense to the TFAP2A gene. Unlike previously reported antisense lncRNAs, HIPSTR expression does not correlate with the expression of its antisense counterpart. Although HIPSTAR and TFAP2A are co-expressed in in vitro derived neural crest and trophoblast cells, only HIPSTAR and not TFAP2A is specifically expressed in a subset of cells within 8-cell- and morula-stage human embryos. We show that, similar to HIPSTAR, in the individual cells of developing human embryos or of stable cell lines the expression of lncRNAs is more highly heterogeneous than the expression of mRNAs. Finally, we demonstrate that HIPSTAR depletion in HEK293 and H1BP, a human embryonic stem cell line, predominantly affects the expression levels of genes involved in early organismal development and cell differentiation. Together, we show that expression of HIPSTAR and hundreds other lncRNAs is highly heterogeneous in human embryos and cell lines. We use HIPSTAR to exemplify the functional relevance of lncRNAs with heterogeneous and developmental stage-specific expression patterns. / Tem sido cada vez mais reconhecido que a transcrição dos genomas eucarióticos produz múltiplos transcritos novos, anteriormente não detectados e ainda não caracterizados, sendo que a maioria é constituida de RNAs não-codificantes longos (lncRNAs) regulatórios. Estudos recentes estão focados principalmente nos lncRNAs transcritos de regiões intergênicas e enhancers; assim, o grupo dos lncRNAs antisenso permanece o menos estudado de todos. Ao mesmo tempo, a transcrição antisenso ocorre em até 74% dos loci de genes humanos, frequentemente - a partir da fita oposta de genes que codificam proteínas envolvidas na regulação da transcrição. No presente trabalho, nós identificamos HIPSTR (Heterogeneously expressed from the Intronic Plus Strand of the TFAP2A-locus RNA), um lncRNA novo conservado que é transcrito a partir da fita antisenso do gene TFAP2A. Ao contrário do anteriormente relatado para os lncRNAs antisenso, a expressão de HIPSTR não está correlacionada com a expressão do gene da fita oposta. HIPSTR e TFAP2A são co-expressos em células da crista neural e em trofoblastos derivadas in vitro, mas somente HIPSTR e não TFAP2A está especificamente expresso num subconjunto de células de embriões humanos nos estágios de 8-células e mórula. Mostramos que, semelhante a HIPSTR, a expressão de lncRNAs é mais altamente heterogênea que a expressão de mRNAs em células individuais de embriões humanos em desenvolvimento ou em linhagens estáveis de células. Finalmente, nós demonstramos que a depleção de HIPSTAR em células HEK293 e H1BP, uma linhagem de células tronco embrionárias humanas, afeta predominantemente os níveis de genes envolvidos no início do desenvolvimento do organismo e na diferenciação de células. No conjunto, nós mostramos que a expressão de HIPSTR e de centenas de outros lncRNAs é altamente heterogênea em embriões humanos e linhagens celulares. Usamos HIPSTR para exemplificar a relevância funcional de lncRNAs com padrões de expressão heterogêneos e estágio-de-desenvolvimento específicos.

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