Publikationsserver der Universitätsbibliothek Marburg
Titel:Identifikation und Charakterisierung neuer Interaktionspartner und Zielgene der Proteinargininmethyltransferase 4
Autor:Streubel, Gundula
Weitere Beteiligte: Renkawitz-Pohl, Renate (Prof.)
Veröffentlicht:2010
URI:https://archiv.ub.uni-marburg.de/diss/z2010/0144
DOI: https://doi.org/10.17192/z2010.0144
URN: urn:nbn:de:hebis:04-z2010-01446
DDC:570 Biowissenschaften, Biologie
Titel (trans.):Identification and characterisation of novel interacting proteins and target genes of the Proteine Arginine Methyltransferase 4
Publikationsdatum:2010-06-24
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
histones, transcriptional regulation, Histone, Chromatin, K562, Proteinargininmethyltransferase, Histon-Methyltransferase, arginine methylation, Transkription <Genetik>, PRMT4, Methylierung, c-Myb, Transkription, HD11, Arginin

Zusammenfassung:
Die Proteinargininmethyltransferase PRMT4 ist als transkriptioneller Coaktivator an der regulierten Expression von Genen während der Ontogenese wichtig. Dabei trägt PRMT4 durch die Methylierung von Argininen im Histon H3 zum Histoncode bei und assoziiert mit weiteren Coaktivatoren, um mit diesen kooperativ die Transkription zu verstärken. Eine Kooperativität zwischen PRMT4 und einer weiteren PRMT, PRMT1, wurde bisher für wenige Transkriptionsfaktoren beschrieben und untersucht. Dem ersten Teil dieser Arbeit lag der Befund einer Microarrayanalyse in HeLa-Zellen zu Grunde. Dieser zeigte, dass PRMT1 und PRMT4 nur dann eine Änderung des Genexpressionprofils hervorriefen, wenn sie zusammen wirkten. Die transkriptionelle Regulation der durch PRMT1 und PRMT4 kooperativ aktivierten Gene CITED2 und KRT8 wurde in der vorgelegten Arbeit genauer analysiert. Es konnte nachgewiesen werden, dass das Cytokin IL-4 in HeLa-Zellen die Phosphorylierung und damit Aktivierung des STAT5- und STAT6-Signalweges sowie eine transkriptionelle Induktion von CITED2 und KRT8 bewirkt. Die IL-4-induzierte Transkription des CITED2-Gens war vom Transkriptionsfaktor STAT5 und den Coaktivatoren PRMT1 und PRMT4 abhängig. Anhand von ChIP-Analysen wurde eine Bindung von PRMT1 und PRMT4 sowie STAT5 an den CITED2-Promotor nach IL-4-Stimulation festgestellt. Die IL-4-induzierte Transkription von CITED2 ging mit der für die Coaktivatorfunktion von PRMT1 und PRMT4 typischenen Argininmethylierungen von Histonen einher. Diese Befunde legten nahe, dass PRMT1 und PRMT4 die Transkription von CITED2 als direkte Coaktivatoren auf der Ebene des Promotors regulieren. Da PRMT1 und PRMT4 mit STAT5 in Abhängigkeit des IL-4-Stimulus interagierten, vermittelt STAT5 vermutlich die Zielgenspezifität der PRMTs für CITED2. In dieser Arbeit wurde damit erstmals eine direkte Coaktivatorfunktion von PRMTs in einem JAK-STAT-Signalweg belegt. PRMT4 übt seine Funktion als Coaktivator durch die Interaktion mit anderen Proteinen oder innerhalb von Komplexen aus. Die Gelfiltrationsanalysen in dieser Arbeit deuteten darauf hin, dass PRMT4 in einem höhermolekularen Komplex vorliegt. Ziel des zweiten Teils der vorgelegten Arbeit war es daher neue Interaktionspartner von PRMT4 zu identifizieren, um bisher unbekannte Funktionen und Signalwege von PRMT4 aufzuzeigen. Die Isolierung endogener PRMT4-Komplexe mittels Ionenaustauscher-Chromatographie und einer anschließenden Affinitätsaufreinigung ermöglichte die massenspektrometrische Identifikation der Proteine Mi-2 und ALIX als neue Interaktionspartner von PRMT4. Die Interaktionen wurden jeweils anhand von unabhängigen Interaktionsstudien verifiziert. Es stellte sich außerdem heraus, dass auch das mit Mi-2 verwandte Protein Mi-2 mit PRMT4 interagiert. Da Mi-2Mi-2 als Mitglieder der Familie der ATP-abhängigen Chromatin-remodeller an der Regulation der Transkription beteiligt sind, ergab sich die Frage nach einer gemeinsamen Funktion mit PRMT4. Eine Assoziation von PRMT4 mit dem Repressorkomplex NuRD, in dem Mi-2 und Mi-2 als integrale Bestandteile auftreten, konnte auf Grund von CoIPs ausgeschlossen werden. Cotransfektions-Assays in der Hühnchen-Makrophagenzelllinie HD11 deckten eine Synergie von PRMT4 und den beiden Mi-2-Proteinen in der Aktivierung der c-Myb-vermittelten Transkription der Gene mim-1 und Lysozym auf. Anhand RNAi-vermittelter Depletionen und ChIP-Analysen in der humanen erythroleukämischen Zelllinie K562 wurde nachgewiesen, dass die c-Myb-Zielgene c-MYC und CDC7 einer aktivierenden und direkten transkriptionellen Regulation durch PRMT4 und Mi-2 unterliegen. Untersuchungen zur biologischen Relevanz der Proteine PRMT4 und Mi-2 in hämatopoetischen Zellen zeigten eine Korrelation mit den c-Myb-vermittelten Effekten auf die Proliferation, den Zellzyklus und die erythroide Differenzierung. Diese Ergebnisse, zusammen mit dem in dieser Arbeit erbrachten Nachweis der Interaktion zwischen c-Myb und PRMT4 bzw. der Mi-2-Proteine, decken PRMT4 und Mi-2 als kooperierende transkriptionelle Coaktivatoren von c-Myb auf. Die Daten lassen den Schluss zu, dass PRMT4 und Mi-2 Regulatoren c-Myb-vermittelter Funktionen sind und somit in die Erythropoese eingreifen.

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