Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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: GSE99932 | GEO | 2018/11/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Project description: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.

2018-11-13 | GSE99931 | GEO

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

2018-11-13 | GSE99934 | GEO

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

2018-11-13 | GSE99930 | GEO

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

2018-11-13 | GSE99885 | GEO

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

2018-11-13 | GSE99945 | GEO

Dynamics of de novo heterochromatin assembly and disassembly at replication forks ensures fork stability

Project description:Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here, we discover a checkpoint regulated cascade of chromatin signaling that activates 5 the histone methyltransferase EHMT2/G9a to catalyze heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fiber approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favored by the G9a-dependent exclusion of the H3K9-demethylase 10 JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering ssDNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help explaining chemotherapy resistance and poor prognosis observed in cancer patients displaying elevated level of G9a/H3K9me3.

2023-05-12 | PXD041742 | Pride

ZFP462 safeguards neural lineage specification by targeting G9A/GLP-mediated heterochromatin to silence enhancers

Project description:ZNF462 haploinsufficiency is linked to Weiss-Kruszka Syndrome, a genetic disorder characterized by neurodevelopmental defects including Autism. Though conserved in vertebrates and essential for embryonic development the molecular functions of ZNF462 remain unclear. We identified its murine homolog ZFP462 in a screen for mediators of epigenetic gene silencing. Here, we show that ZFP462 safeguards neural lineage specification of mouse embryonic stem cells (ESCs) by targeting the H3K9-specific histone methyltransferase complex G9A/GLP to silence mesoendodermal genes. ZFP462 binds to transposable elements (TEs) that are potential enhancers harboring ESC-specific transcription factor (TF) binding sites. Recruiting G9A/GLP, ZFP462 seeds heterochromatin, restricting TF binding. Loss of ZFP462 in ESCs results in increased chromatin accessibility at target sites and ectopic expression of mesoendodermal genes. Taken together, ZFP462 confers lineage- and locus-specificity to the broadly expressed epigenetic regulator G9A/GLP. Our results suggest that aberrant activation of lineage non-specific genes in the neuronal lineage underlies ZNF462-associated neurodevelopmental pathology.

2023-05-10 | PXD037238 | Pride

Distinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti–PD-1 Immunotherapy in Endometrial Carcinoma

Project description:Responses to immune checkpoint blockade (ICB) are variable among mismatch repair-deficient (MMRd) cancers. We completed a phase 2 clinical trial of the PD-1 inhibitor pembrolizumab in 24 patients with MMRd endometrial cancer (NCT02899793). Patients with mutational MMRd tumors (6 patients) had higher response rates and longer survival than those with epigenetic MMRd tumors (18 patients). Mutation burden was higher in tumors with mutational MMRd compared to epigenetic MMRd; however, within each category of MMRd, mutation burden was not associated with ICB response. Notably, JAK1 mutations did not confer resistance to pembrolizumab. Longitudinal single-cell RNA-seq of circulating immune cells revealed contrasting modes of anti-tumor immunity against mutational and epigenetic MMRd cancers. Whereas effector CD8+ T cell responses correlated with regression of mutational MMRd tumors, highly active CD16+ NK cells were associated with ICB-responsive epigenetic MMRd tumors. These data highlight the interplay between tumor-intrinsic and extrinsic factors that influence ICB response.

2022-10-07 | GSE212217 | GEO

G9a plays distinct roles in maintaining DNA methylation, retrotransposon silencing and chromatin looping

Project description:G9a is a lysine methyltransferase that regulates epigenetic modifications, transcription and genome organization. However, whether these properties are dependent on one another or represent distinct functions of G9a remains unclear. In this study, we observe widespread DNA methylation loss in G9a depleted and catalytic mutant embryonic stem cells. Furthermore, we define how G9a regulates chromatin accessibility, epigenetic modifications and transcriptional silencing in both catalytic dependent and independent manners. Reactivated retrotransposons provide alternative promoters and splice sites leading to upregulation of neighboring genes and production of chimeric transcripts. Moreover, while topologically associated domains and compartments A/B definitions are largely unaffected, the loss of G9a leads to altered chromatin states, aberrant CTCF and cohesin binding, and differential chromatin looping especially at retrotransposons. Taken together, our findings reveal how G9a regulates the epigenome, transcriptome and higher-order chromatin structures in distinct mechanisms.

2020-10-26 | GSE138102 | GEO

Project description:Tumor mutational burden and aneuploidy

| PRJNA610493 | ENA