Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours

ABSTRACT: Mutations 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-depleted tumours also display pronounced genomic instability and a frequent accumulation of loss-of-function p53 mutations, compared to their wild-type counterparts. Our results therefore provide evidence for a causal link between chromatin modifications and mutational load in tumours and call for caution when assessing the long-term therapeutic benefits of inhibiting epigenetic factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE99945 | GEO | 2018/11/13

REPOSITORIES: GEO