In silico analysis of Polycomb/Trithorax response elements in Drosophila and mammals based on DynScan : an alignment independent sensitivity increasing framework for cross-species prediction of regulatory elements

Hauenschild A (2008)
Bielefeld (Germany): Bielefeld University.

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Bielefeld Dissertation | English
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Rehmsmeier, Marc (Dr.)
Abstract
Cis-regulatorische Elemente besitzen eine Vielzahl verschiedener Bindestellen für Aktivatoren und Repressoren der Transkription. Eine Art dieser Elemente sind Verstärker, die Genexpressionsmuster bestimmen, und Polycomb/Trithorax Response Elements (PREs). Diese übernehmen die Funktion der Enhancer und erhalten die Genexpressionsmuster hunderter Gene aufrecht, die besonders wichtig für die Zellentwicklung sind. PREs sind essentiell für die korrekten Identitäten von sowohl Stammzellen als auch differenzierten Zellen. Evolutionäre Unterschiede in cis-regulatorischen Elementen sind eine grosse Quelle phänotypischer Unterschiede, und funktioniale Bindestellen innerhalb regulatorischer Elemente zeigen eine starke Diversität. Dennoch sind evolutionäre Prozesse, die über Änderungen der Bindestellen hinausgehen, schwer zu analysieren. In dieser Arbeit präsentieren wir einen kombinierten Ansatz aus genomweiter bioinformatischer Analyse und experimenteller Kontrolle ausgewählter Regionen, mit dem Ziel, PRE Evolution in verschiedenen Drosophila Spezies auszuwerten. Unsere Ergebnisse zeigen eine extrem dynamische Evolution von PREs. Erstens zeigen wir, dass die Anzahl der PREs dramatisch zwischen verschiedenen Spezies schwankt. Zweitens weisen wir nach, dass die funktionialen Bindestellen innerhalb der PREs auch in konservierten Bereichen starke Unterschiede aufweisen. Und drittens zeigen wir, dass PREs in nicht orthologen Bereichen in konservierten Gene loci gefunden werden. Durch den Nachweis, dass PRE Evolution nicht auf die Adaption bereits bestehender Elemente beschränkt ist, demonstrieren wir eine neue Dimension cis-regulatorischer Evolution.

Cis-regulatory DNA elements contain multiple binding sites for activators and repressors of transcription. Among these elements are enhancers, which establish gene expression states, and Polycomb/Trithorax response elements (PREs), which take over from enhancers and maintain transcription states of several hundred developmentally important genes. PREs are essential to the correct identities of both stem cells and differentiated cells. Evolutionary differences in cis-regulatory elements are a rich source of phenotypic diversity, and functional binding sites within regulatory elements turn over rapidly in evolution. However, more radical evolutionary changes that go beyond motif turnover have been difficult to assess. Here we use a combination of genome wide bioinformatic prediction and experimental validation at specific loci, to evaluate PRE evolution across four Drosophila species. Our results show that PRE evolution is extraordinarily dynamic. Firstly, we show that the numbers of PREs differ dramatically between species. Secondly, we demonstrate that functional binding sites within PREs at conserved positions turn over rapidly in evolution, as has been observed for enhancer elements. Finally, although it is theoretically possible that new elements can arise out of non functional sequence, evidence that they do so is lacking. We show here that functional PREs are found at non-orthologous sites in conserved gene loci. By demonstrating that PRE evolution is not limited to the adaptation of pre-existing elements, these findings document a novel dimension of cis-regulatory evolution.
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Hauenschild A. In silico analysis of Polycomb/Trithorax response elements in Drosophila and mammals based on DynScan : an alignment independent sensitivity increasing framework for cross-species prediction of regulatory elements. Bielefeld (Germany): Bielefeld University; 2008.
Hauenschild, A. (2008). In silico analysis of Polycomb/Trithorax response elements in Drosophila and mammals based on DynScan : an alignment independent sensitivity increasing framework for cross-species prediction of regulatory elements. Bielefeld (Germany): Bielefeld University.
Hauenschild, A. (2008). In silico analysis of Polycomb/Trithorax response elements in Drosophila and mammals based on DynScan : an alignment independent sensitivity increasing framework for cross-species prediction of regulatory elements. Bielefeld (Germany): Bielefeld University.
Hauenschild, A., 2008. In silico analysis of Polycomb/Trithorax response elements in Drosophila and mammals based on DynScan : an alignment independent sensitivity increasing framework for cross-species prediction of regulatory elements, Bielefeld (Germany): Bielefeld University.
A. Hauenschild, In silico analysis of Polycomb/Trithorax response elements in Drosophila and mammals based on DynScan : an alignment independent sensitivity increasing framework for cross-species prediction of regulatory elements, Bielefeld (Germany): Bielefeld University, 2008.
Hauenschild, A.: In silico analysis of Polycomb/Trithorax response elements in Drosophila and mammals based on DynScan : an alignment independent sensitivity increasing framework for cross-species prediction of regulatory elements. Bielefeld University, Bielefeld (Germany) (2008).
Hauenschild, Arne. In silico analysis of Polycomb/Trithorax response elements in Drosophila and mammals based on DynScan : an alignment independent sensitivity increasing framework for cross-species prediction of regulatory elements. Bielefeld (Germany): Bielefeld University, 2008.
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