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The Global ETD Search service is a free service for researchers
to find electronic theses and dissertations. This service is
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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.
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Showing 451 to 456 of 456 (0.05 seconds)| 451 |
The mechanisms of BPA exposure and in the developing mammary glandHindman, Andrea R. January 2017 (has links)
No description available.
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Experimental and theoretical analysis of X-chromosome inactivation as a paradigm for epigenetic memory and molecular decision-makingMutzel, Verena 19 October 2021 (has links)
X-Chromosom-Inaktivierung (XCI) ist der Mechanismus, den Säuger zur Dosiskompensierung zwischen weiblichen und männlichen Zellen verwenden. XCI wird ausgelöst durch die monoallelische Hochregulation der langen nicht-kodierenden RNA Xist von einem der zwei X-Chromosomen in weiblichen Zellen. Die Xist RNA vermittelt dann das Ausschalten der Gene auf diesem X-Chromosom. Das wirft einige interessante Fragen auf: Wie zählen Zellen ihre X-Chromosomen und stellen sicher, dass genau eines aktiv bleibt? Wie entscheiden sie, welches X-Chromosom aktiv bleibt und welches ausgeschaltet wird? Und wie erinnern sie sich an diese Entscheidung und behalten sie stabil bei durch alle weiteren Zellteilungen?
Mithilfe eines stochastischen Modells zeigen wir, dass diese XCI Regulation prinzipiell durch nur zwei Regulatoren erklärt werden kann: Ein global (in trans) agierender XCI Aktivator und ein lokal (in cis) agierender XCI Repressor. Dieses Netzwerk aus nur zwei Regulatoren kann die Xist Expressionsmuster in verschiedenen Säugerspezies reproduzieren, von der Maus bis zum Mensch. Es sagt außerdem voraus, dass Zellen in der Lage sind, biallelische zu monoallelischer Xist Expression zu korrigieren, eine Vorhersage, für die wir tatsächlich experimentelle Belege finden. Mit einem mechanistischen Modell zeigen wir, dass das cis-Gedächtnis über den Xist Expressionszustand durch Antisense-Transkription zustande kommen könnte. Auf dieser Hypothese aufbauend untersucht der zweite Teil der Arbeit das Potential von Antisense-Transkription, ein lokales Gedächtnis über den Expressionszustand eines Gens zu generieren, genauer. Diese Analyse sagt vorher, dass Antisense-Repression den Expressionszustand eines Lokus tatsächlich für einige Tage stabil erhalten kann. / X-chromosome inactivation (XCI) is the mechanism for dosage compensation between the sexes in mammals. It is initiated through monoallelic upregulation of the long non-coding RNA Xist from one X chromosome, which mediates almost complete transcriptional silencing of this X chromosome. XCI regulation raises intriguing and thus far unanswered questions: How do cells count their X chromosomes and ensure that exactly one stays active? How do they make a mutually exclusive choice for one inactive X chromosome, and how do they then stably maintain this choice throughout subsequent cell divisions?
Using stochastic modeling, we show that XCI onset only requires two regulators: A trans-acting Xist activator that ensures female specificity and a cis-acting Xist repressor that allows stable maintenance of alternative Xist expression states. This two-regulator network can recapitulate Xist expression patterns across different species and makes a novel prediction that is validated experimentally: Cells are able to revert biallelic Xist expression to monoallelic expression. With a mechanistic stochastic model we show that Xist's antisense transcript Tsix might be the cis-acting Xist repressor, uncovering the molecular mechanism behind the stabilization of the alternative Xist expression states. Building upon Tsix' possible functional role in stabilizing alternative Xist expression states on the active and inactive X chromosome, the second part of this thesis investigates the potential of antisense transcription to maintain a transient transcriptional memory. We find that mutual repression between a pair of antisense genes can allow the locus to remember the transcription state it has acquired due to a past signal for several days.
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Genetic and epigenetic profiles of elderly AML / Acute myeloid leukemia in the elderly is characterized by a distinct genetic and epigenetic landscapeSantos Silva, Patricia Alexandra 19 July 2019 (has links)
Die molekulare Charakterisierung von genetischen Veränderungen der Akuten Myeloischen Leukämie (AML) wurde vor allem bei jungen Patienten vorangebracht, hingegen fehlen Analysen für die AML bei älteren Patienten. Entsprechend ergab sich die Rationale, genetische und epigenetische Alterationen bei älteren AML Patienten zu untersuchen, um spezifische Signaturen zu identifizieren. Wir untersuchten ältere 93 AML Patienten aus dem Study Alliance Leukemia (SAL) Register. Es wurden 555 Gene auf der Illumina HiSeq2000 Plattform sequenziert und DNA Methylierungsprofile mittels dem Illumina 450K Array untersucht.
Insgesamt wurden 814 molekulare Alterationen in 281 Genen detektiert. Besonders hohe Mutationsfrequenzen wurden in den Genen DNMT3A (33%), TET2 (24%), SRSF2 (23%) und ASXL1 (21%) notiert. Alterationen in epigenetischen Regulatoren (85%) und in Genen, die in Splicing involviert sind (38%), wurden gehäuft beobachtet. Ältere AML Patienten mit Mutationen in DNMT3A oder DNA Reparaturgenen wiesen eine geringere Lebenserwartung im Vergleich zu der restlichen Kohorte auf.
Wir verglichen die Meythlierungsdaten aus der SAL mit denen der TCGA Kohorte, umso die Methylierungsmuster von älteren mit denen von jüngeren Patienten zu differenzieren. Es konnte ein distinktes Methylierungsprofil in den DNA Proben von älteren AML Patienten nachgewiesen werden. Die im Vergleich zu jüngeren AML Patienten unterschiedlich methylierten Regionen bei älteren AML Patienten überlappten mit Genen verschiedener Signalwege, die Hallmarks von Alterungsprozessen und Krebs entsprechen.
Zusammenfassend konnten wir für die Kohorte älterer AML Patienten genetische Alterationen nachweisen und mit spezifischen Profilen von Mutationen in epigenetischen Regulatoren korrelieren. Diese molekulare Kategorisierung unterstreicht distinkte biologische Mechanismen in älteren AML Patienten und die Notwendigkeit von spezifischen Therapieansätzen für diese Kohorte mit ungünstiger Prognose. / Despite advances in the characterization of molecular alterations in younger acute myeloid leukemia (AML) patients, comprehensive studies in elderly AML are lacking. Thus, we investigated genetic and epigenetic alterations and probed for specific signatures to understand the unfavorable outcomes of elderly AML. We studied 93 AML patients (65 to 90 years old), enrolled in the Study Alliance Leukemia registry (SAL). To capture a broad spectrum of alterations, we sequenced 555 genes on an Illumina HiSeq2000 platform and investigated DNA methylation profiles using the Illumina 450K array.
Overall, we detected 814 molecular alterations in 281 genes, with a median of 7 genes mutated per patient. Particularly high mutation frequencies were identified for DNMT3A (33%), TET2 (24%), SRSF2 (23%) and ASXL1 (21%). We observed frequent alterations in epigenetic regulators (85%) and in splicing factors (38%). Notably, SAL elderly AML patients with mutations in DNMT3A or DNA repair genes (in absence of mutations in NPM1 or splicing factors) had an inferior survival of only 9 months (compared to 17 months for the remaining patients).
In addition, for the analysis of elderly AML DNA methylation, we integrated the SAL cohort with TCGA methylation data for comparisons of methylation levels to younger patients. A distinct DNA methylation profile was observed in older AML patients, which correlated with the presence of mutations in IDH1/2, RUNX1 and ASXL1 and epigenetic similarities with TP53/Complex samples. The differential methylated regions of elderly AML (compared to younger AML samples) were shown to overlap genes from several pathways that are hallmarks of both age and cancer.
In conclusion, we unraveled distinct patterns of genetic alterations and correlated specific epigenetic profiles of elderly AML to high rate mutated epigenetic regulators. This molecular categorization underscored the distinct biology and the need for specific therapeutic approaches in elderly AML.
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A Novel Approach to Identify Candidate Imprinted Genes in HumansShapiro, Jonathan 21 March 2012 (has links)
Many imprinted genes are necessary for normal human development. Approximately 70 imprinted genes have been identified in humans. I developed a novel approach to identify candidate imprinted genes in humans using the premise that imprinted genes are often associated with nearby parent-of-origin-specific DNA differentially methylated regions (DMRs). I identified parent-of-origin-specific DMRs using sodium bisulfite-based DNA (CpG) methylation profiling of uniparental tissues, mature cystic ovarian teratoma (MCT) and androgenetic complete hydatidiform mole (AnCHM), and biparental tissues, blood and placenta. In support of this approach, the CpG methylation profiling led to the identification of parent-of-origin-specific differentially methylated CpG sites (DMCpGs) in known parent-of-origin-specific DMRs. I found new DMRs for known imprinted genes NAP1L5 and ZNF597. Most importantly, I discovered many new DMCpGs, which were associated with nearby genes, i.e., candidate imprinted genes. Allelic expression analyses of one candidate imprinted gene, AXL, suggested polymorphic imprinting of AXL in human blood.
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A Novel Approach to Identify Candidate Imprinted Genes in HumansShapiro, Jonathan 21 March 2012 (has links)
Many imprinted genes are necessary for normal human development. Approximately 70 imprinted genes have been identified in humans. I developed a novel approach to identify candidate imprinted genes in humans using the premise that imprinted genes are often associated with nearby parent-of-origin-specific DNA differentially methylated regions (DMRs). I identified parent-of-origin-specific DMRs using sodium bisulfite-based DNA (CpG) methylation profiling of uniparental tissues, mature cystic ovarian teratoma (MCT) and androgenetic complete hydatidiform mole (AnCHM), and biparental tissues, blood and placenta. In support of this approach, the CpG methylation profiling led to the identification of parent-of-origin-specific differentially methylated CpG sites (DMCpGs) in known parent-of-origin-specific DMRs. I found new DMRs for known imprinted genes NAP1L5 and ZNF597. Most importantly, I discovered many new DMCpGs, which were associated with nearby genes, i.e., candidate imprinted genes. Allelic expression analyses of one candidate imprinted gene, AXL, suggested polymorphic imprinting of AXL in human blood.
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Role of Ring1B in ephitelial to mesenchimal transition, invasion and migration of mammary epithelial cellsBosch Gutiérrez, Almudena 21 December 2009 (has links)
The Polycomb group (PcG) family of proteins form chromatin-modifying complexes essential for embryonic development, and stem cell renewal and are commonly deregulated in cancer. There are several reports that address the possible implication of PcG proteins in tumor progression and metastasis, but very little is known about the specific role of these proteins in tumor progression and invasion. On the other hand, the molecular processes of the worst cancer prognosis, metastasis, which leads to an incurable disease, are yet incompletely elucidated. Here we show a role for Ring1B, a PcG protein, in three processes related to metastasis: in the Epithelial-mesenchymal transition (EMT), a critical morphogenic event that occurs during embryonic development and during the progression of various epithelial tumors, an in the migration and the invasion of mammary epithelial cells. / Las proteínas del grupo Polycomb (PcG) forman complejos modificadores de la cromatina esenciales en el desarrollo embrionario y en la renovación de las células madre, y su desregulación ha sido asociada al cáncer. Varios estudios muestran la posible implicación de las proteínas de PcG en la progresión tumoral y en la metástasis, pero a pesar de ello se sabe muy poco de los procesos moleculares en los que estas proteínas están participando. Por otro lado, los procesos moleculares responsables del peor pronóstico en cáncer, la metástasis, que continua siendo una enfermedad incurable, siguen sin estar completamente elucidados. En esta disertación mostramos el papel de Ring1B, una proteína del PcG, en tres procesos implicados en la metástasis: en la transición epitelio-mesénquima (EMT), un proceso morfogénico crítico en el desarrollo embrionario y durante la progresión de varios cánceres epiteliales, y en la migración y la invasión de las células epiteliales mamarias.
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