GSE99931 Chromatin opening alters the mutational context and promotes tumour progression through selection of genomically-unstable p53-mutant cells (interfollicular epidermis cells)

Contributors : Alexandra Avgustinova ; Aikaterini Symeonidi ; Lloren ç Solé ; Mercé Martín ; Andrés Castellanos ; Neus Prats ; Fran Supek ; Ben Lehner ; Salvador Aznar BenitahSeries Type : Expression profiling by arrayOrganism : Mus musculusMutations and expression changes of epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive as antitumour targets. However, the mutational landscape of tumours correlates with the chromatin state of their cell-of-origin, raising the concern that targeting epigenetic factors might alter the mutational burden and possibly aggravate disease progression. Nonetheless, a causal link between changes in chromatin in tissues and the mutational landscape of their cognate tumours has not yet been established. Here we show that increasing chromatin accessibility through a conditional deletion of the histone H3K9 methyltransferase G9a severely delays and reduces carcinogen-induced squamous tumour initiation and burden. Strikingly, after a prolonged latency, G9a-mutant mice develop highly aggressive tumours with an expanded cancer stem cell (SC) pool. Loss of G9a leads to extensive chromatin opening in the cells of origin of these tumours (i.e. epidermal and hair follicle SCs) . Although this does not alter the number of single-nucleotide variants, the type of substitutions, or the overall mutational topography, it significantly changes the mutational signatures (i.e. microcontext) in the tumor cells. G9a-...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Mus musculus Source Type: research