Polycomb Group of proteins are essential factors present in cells’ nuclei. These multiprotein complexes are key repressive chromatin factors that regulate cellular differentiation during development, contributing to the correct establishment of lineage-specific transcriptional programs. Moreover, they represent key factors of proliferation and deregulation of their levels and activity have been linked to the onset and development of several human cancers. Recently, gain of function heterozygous EZH2 mutations have been discovered in non-Hodgkin lymphomas and melanomas. These mutations cause an aminoacidic substitution within the EZH2 catalytic SET domain (Y641), resulting in increased H3K27me3 deposition. Very little is known about this mutated enzyme, therefore the aim of my thesis is trying to unravel the tumorigenic mechanisms underlying these mutations. To understand a general oncogenic role for this mutated enzyme, we used MEF as an alternative, simpler model system. We observed increased deposition of H3K27me3 without any relevant transcriptional alteration at steady state, confirming our results also in lymphoma cell lines. To investigate a cooperative transcriptional deregulation for mutant EZH2, we then subjected MEFs to three different stimuli (starvation, myc upregulation and reprogramming to pluripotency). Since we found this to be true only during cell-fate transition, we proposed a model in which the levels of the H3K27me3 are increasingly deposited where the mark is already present at steady state. This could be relevant in lymphomas, impeding centroblasts differentiation and resulting in tumorigenesis in the presence of concomitant oncogenic mutations. This observation could shed light on the molecular mechanisms underlying lymphomagenesis in patients.
THE ROLE OF ENHANCED POLYCOMB REPRESSIVE COMPLEX 2 ACTIVITY IN TUMORIGENESIS / L. Cedrone ; internal advisor: S. CHIOCCA ; external advisor: A. BRACKEN ; supervisor: D. PASINI. - Milano : Università degli studi di Milano. UNIVERSITA' DEGLI STUDI DI MILANO, 2017 Mar 02. ((28. ciclo, Anno Accademico 2016.
|Titolo:||THE ROLE OF ENHANCED POLYCOMB REPRESSIVE COMPLEX 2 ACTIVITY IN TUMORIGENESIS|
|Tutor esterno:||PASINI, DIEGO|
|Supervisori e coordinatori interni:||MINUCCI, SAVERIO|
|Data di pubblicazione:||2-mar-2017|
|Parole Chiave:||chromatin; Polycomb Repressive complexes; H3K27me3; non-Hodgkin lymphomas; tumors; catalytic dysregulation; transcriptional regulation; reprogramming|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Citazione:||THE ROLE OF ENHANCED POLYCOMB REPRESSIVE COMPLEX 2 ACTIVITY IN TUMORIGENESIS / L. Cedrone ; internal advisor: S. CHIOCCA ; external advisor: A. BRACKEN ; supervisor: D. PASINI. - Milano : Università degli studi di Milano. UNIVERSITA' DEGLI STUDI DI MILANO, 2017 Mar 02. ((28. ciclo, Anno Accademico 2016.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/l-cedrone_phd2017-03-02|
|Appare nelle tipologie:||Tesi di dottorato|