First name
Laura
Last name
Cedrone
Year of Study
Research Center
Thesis Title
The role of enhanced Polycomb Repressive Complex2 activity in tumorigenesis
Thesis Abstract
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.
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.
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