Publikationsserver der Universitätsbibliothek Marburg

Titel:Charakterisierung der Repressorfunktion von PRMT6 und deren Rolle bei der Differenzierung, Proliferation und Seneszenz
Autor:Stein, Claudia
Weitere Beteiligte: Renkawitz-Pohl, Renate (Prof. Dr.)
Veröffentlicht:2011
URI:https://archiv.ub.uni-marburg.de/diss/z2011/0068
URN: urn:nbn:de:hebis:04-z2011-00685
DOI: https://doi.org/10.17192/z2011.0068
DDC: Biowissenschaften, Biologie
Titel (trans.):Characterization of the repressive function of PRMT6 and its role in differentiation, proliferation and senescence
Publikationsdatum:2011-03-03
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Gene regulation, PRMT6, Arginine methylation, Transkription, PRMT6, Genregulation, Transcription, Argininmethylierung

Zusammenfassung:
PRMT6 gehört zur Familie der Protein-Arginin-Methyltransferasen und wurde 2002 durch genomweite Suche nach neuen PRMT Mitgliedern anhand der konservierten katalytischen Domäne gefunden und als nukleär lokalisiertes Enzym identifiziert. Obwohl bereits einige Substrate von PRMT6 beschrieben wurden, ist über die genaue Funktion des Enzyms wenig bekannt. Die vorliegende Arbeit hatte zum Ziel neue Chromatinfunktionen von PRMT6 aufzudecken und zu charakterisieren. In der vorliegenden Arbeit wurden zunächst das Vorkommen und die Relevanz der PRMT6-vermittelten H3R2 Dimethylierung in vivo nachgewiesen. Es wurde gezeigt, dass die H3R2 Dimethylierung durch PRMT6 die aktive Histonmodifikation H3K4me3 antagonisiert und darüber die Repression einiger HOXA Gene und c-Myc-Zielgene erreicht wird. In nachfolgenden Untersuchungen wurde der Antagonismus zwischen H3R2me2 und H3K4me3 am HOXA2 Gen mechanistisch aufgeklärt. Die PRMT6-vermittelte H3R2 Dimethylierung inhibiert die H3K4 Trimethylierung, indem die Chromatinrekrutierung der Untereinheiten des H3K4-Methyltransferase Komplexes MLL1 und WDR5 verhindert wird. Es wurde gezeigt, dass die transkriptionelle Repression von HOXA2 durch PRMT6 auch bei der neuronalen Differenzierung von NT2/D1 Zellen von Bedeutung ist. Weitere Untersuchungen im Rahmen dieser Arbeit beschäftigten sich mit der Aufklärung einer potentiellen positiven Wechselwirkung zwischen PRMT6 und PcG Proteinen. Dabei wurde gefunden, dass PRMT6 mit PcG Proteinen interagiert und ähnlich wie die PcG Proteine zum Erhalt des spezifischen Expressionsmusters der HOXA Gene während der neuronalen Differenzierung beiträgt. Ähnlich wie die Depletion von PcG Proteinen führte die Depletion von PRMT6 zur Hyperaktivierung der anterior lokalisierten HOXA Gene und zur Derepression der posterior lokalisierten HOXA Gene nach Induktion der Differenzierung in NT2/D1 Zellen mit ATRA. Diese Fehlregulation der HOXA Gene als Folge der PRMT6 Depletion ging mit einem veränderten Histonmodifikationsmuster einher. PRMT6-defiziente Zellen wiesen eine Zunahme der aktiven Histonmodifikation H3K4me3 und einen Verlust der repressiven Histonmodifikation H3K27me3 auf. Zusammenfassend identifizieren diese Daten PRMT6 als transkriptionellen Repressor durch die Katalyse der H3R2 Dimethylierung. Diesem Repressionsmechanismus liegt die Wechselwirkung zwischen Histon-Argininmethylierung und Histon-Lysinmethylierung zugrunde. Aufgrund der Tatsache, dass PcG Proteine durch direkte Regulation des INK4B-ARF-INK4A Lokus mit der Regulation von Proliferation und Seneszenz in Verbindung gebracht werden, wurde im Folgenden untersucht, ob PRMT6 den INK4B-ARF-INK4A Lokus ebenfalls reguliert. Der Verlust von PRMT6 in humanen diploiden Fibroblasten (TIG3-T) führte zu einem Proliferationsarrest, der durch eine Akkumulation von G1-Phase Zellen gekennzeichnet war. Darüber hinaus resultierte die Depletion von PRMT6 in zellulärer Seneszenz, die durch die Aktivität von Seneszenz-assoziierter beta-Galaktosidase nachgewiesen wurde, und in einer Hochregulation der CDK-Inhibitoren p16/INK4A und CDKN1A (p21/CIP1). In Übereinstimmung damit führte eine Depletion von PRMT6 in Tumorzellen zur Reduktion des klonogenen Potentials. Zusammenfassend weisen diese Daten darauf hin, dass PRMT6 für die Proliferation von humanen diploiden Fibroblasten und Tumorzellen benötigt wird und durch transkriptionelle Regulation wichtiger Zellzyklusregulatoren Seneszenz inhibiert. Abschließend wurde ein unvoreingenommener Ansatz zur Aufreinigung neuer Interaktionspartner von PRMT6 unter Verwendung von TAP (Tandem Affinity Purification)-markiertem PRMT6 etabliert. Die coaufgereinigten Interaktionspartner wurden mittels massenspektrometrischer Analyse identifiziert und mit Hilfe der Datenbank STRING sowie Literaturrecherche auf publizierte Zusammenhänge zwischen den möglichen Interaktionspartnern, Argininmethylierung und PRMT6 analysiert. Diese Ergebnisse können als Ausgangspunkt für die zukünftige Erforschung von PRMT6 dienen und zur Erweiterung des Verständnisses weiterer nukleärer Funktionen von PRMT6 beitragen.

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