Histone H3 mutant and Polycomb Repressive Complex 2 role in Diffuse Intrinsic Pontine Gliomas

Project: Research project

Project Details

Description

The correct establishment of cell-type specific transcription programs is of fundamental importance for
proper embryonic development as well as to ensure correct cellular differentiation for tissue homeostasis in
adult organisms. Regulation of cellular identity is at the basis of several human pathologies with a particular
importance in the development of human cancers. The correct regulation of chromatin modifications plays a
crucial role in these processes. Indeed, chromatin-modifying factors (also defined as epigenetic factors) often
play essential roles in regulating normal development and differentiation and have been recently classified
among the most mutated pathways in human cancers. Ensuring maintenance of gene repression is as
important as establishing the activation of lineage specific genes. Polycomb group proteins (PcG) are critical
for this and are among the most important gatekeepers that ensure the correct establishment and maintenance
of cellular identity in metazoans. Indeed, the activity of PcG proteins is frequently altered in several human
tumours via different genetic, transcriptional and epigenetic alteration whose mechanistic role remains
poorly understood. PcGs exist in two distinct multi-protein repressive complexes (PRC1 and PRC2) that, by
post-transnationally modifying respectively histone H2A and histone H3, control in large part redundant
transcriptional pathways. While PRC2 methylates (me) histone H3 on lysine (K) 27, the PRC1 complex
mono-ubiquitylates histone H2A on K119 (H2Aubq). Both activities are linked with transcriptional
repression and chromatin compaction. The catalytic subunit of PRC2 is the methyltrasferase EZH2 (in some
cases compensated by the activity of its paralogue EZH1) and requires stable association with the core
members of the complex Eed and Suz12. The PRC2 members are generally regarded as negative prognostic
factors in different tumours such as brain tumours (e.g. glioblastoma). However, recently, a high recurrent
lysine-to-methionine somatic mutation on histone H3.3 (K27M) has been reported to globally inhibit PRC2
enzymatic activity in pediatric Diffused Intrinsic Pontine Gliomas (DIPGs). These findings indirectly support
a tumour-suppressive function of the PRC2 in those tumours. Furthermore this generates a potentially serious
drawback on the efficacy (or dangerousness) of PRC2 inhibitors for these specific type of tumours. This
project aims to characterize the molecular and biological proprieties of the frequent histone H3.3 somatic
mutation identified in DIPGs (K27M), its oncogenic potential and its relationship with the PRC2 role in
those tumours.
StatusFinished
Effective start/end date3/1/163/9/18

Funding

  • Italian Association for Cancer Research (Agmt Signed 3/10/16)

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