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| Status |
Public on Nov 13, 2018 |
| Title |
Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
Gene expression analysis of homeostatic skin it G9a Wt and G9a cKO mice
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| Contributor(s) |
Avgustinova A, Symeonidi A, Solé L, Martín M, Castellanos A, Prats N, Supek F, Lehner B, Aznar Benitah S |
| Citation(s) |
30455462 |
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| Submission date |
Jun 12, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Aikaterini Symeonidi |
| E-mail(s) |
[email protected]
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| Organization name |
Institut for Research in Biomedicine (IRB-Barcelona)
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| Department |
Oncology
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| Lab |
Stem cells and Cancer Lab
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| Street address |
Baldiri i Reixac, 10
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| City |
Barcelona |
| State/province |
Barcelona |
| ZIP/Postal code |
08028 |
| Country |
Spain |
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| Platforms (1) |
| GPL11180 |
[HT_MG-430_PM] Affymetrix HT MG-430 PM Array Plate |
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| Samples (14)
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| GSM2665429 |
Homeostatic epidermis bulge cells in G9a cKO, replicate 1 |
| GSM2665430 |
Homeostatic epidermis bulge cells in G9a cKO, replicate 2 |
| GSM2665431 |
Homeostatic epidermis bulge cells in G9a cKO, replicate 3 |
| GSM2665432 |
Homeostatic epidermis bulge cells in G9a cKO, replicate 4 |
| GSM2665433 |
Homeostatic epidermis bulge cells in G9a WT, replicate 1 |
| GSM2665434 |
Homeostatic epidermis bulge cells in G9a WT, replicate 2 |
| GSM2665435 |
Homeostatic epidermis bulge cells in G9a WT, replicate 3 |
| GSM2665436 |
Homeostatic epidermis IFE cells in G9a cKO, replicate 1 |
| GSM2665437 |
Homeostatic epidermis IFE cells in G9a cKO, replicate 2 |
| GSM2665438 |
Homeostatic epidermis IFE cells in G9a cKO, replicate 3 |
| GSM2665439 |
Homeostatic epidermis IFE cells in G9a cKO, replicate 4 |
| GSM2665440 |
Homeostatic epidermis IFE cells in G9a WT, replicate 1 |
| GSM2665441 |
Homeostatic epidermis IFE cells in G9a WT, replicate 2 |
| GSM2665442 |
Homeostatic epidermis IFE cells in G9a WT, replicate 3 |
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| This SubSeries is part of SuperSeries: |
| GSE99956 |
Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours |
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| Relations |
| BioProject |
PRJNA390167 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE99934_RAW.tar |
31.2 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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