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BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network [ATAC-seq]

ABSTRACT: Chromatin accessibility profiling by high throughput sequencing

ORGANISM(S): Homo sapiens

PROVIDER: GSE199364 | GEO | 2022/09/16

REPOSITORIES: GEO

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BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.

Project description:Inhibition of the tumour suppressive function of p53 (encoded by TP53) is paramount for cancer development in humans. However, p53 remains unmutated in the majority of cases of glioblastoma (GBM)-the most common and deadly adult brain malignancy1,2. Thus, how p53-mediated tumour suppression is countered in TP53 wild-type (TP53WT) GBM is unknown. Here we describe a GBM-specific epigenetic mechanism in which the chromatin regulator bromodomain-containing protein 8 (BRD8) maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex. This mechanism causes a repressive chromatin state that prevents transactivation by p53 and sustains proliferation. Notably, targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility and engages p53 transactivation. This in turn enforces cell cycle arrest and tumour suppression in TP53WT GBM. In line with these findings, BRD8 is highly expressed with H2AZ in proliferating single cells of patient-derived GBM, and is inversely correlated with CDKN1A, a canonical p53 target that encodes p21 (refs. 3,4). This work identifies BRD8 as a selective epigenetic vulnerability for a malignancy for which treatment has not improved for decades. Moreover, targeting the bromodomain of BRD8 may be a promising therapeutic strategy for patients with TP53WT GBM.

| S-EPMC10189659 | biostudies-literature

BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network [RNA-seq]

Project description:Transcriptome analysis by high throughput sequencing

2022-09-16 | GSE158550 | GEO

BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network [ChIP-seq]

Project description:Genome-wide binding/occupancy profiling by high throughput sequencing

2022-09-16 | GSE158549 | GEO

BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-09-15 | GSE158551 | GEO

BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network [ATAC-seq]

Project description:BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network [ATAC-seq]

| PRJNA819459 | ENA

BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network

Project description:BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network

| PRJNA665550 | ENA

BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network [ChIP-seq]

Project description:BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network [ChIP-seq]

| PRJNA665554 | ENA

BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network [RNA-seq]

Project description:BRD8 maintains glioblastoma by epigenetic reprogramming of the P53 network [RNA-seq]

| PRJNA665555 | ENA

Chromatin accessibility-based epigenetic landscape in osteoclastogenesis [ATAC-seq]

Project description:In this study, we showed chromatin accessibility-based epigenetic landscape in osteoclastogenesis. To reveal chromatin accessibility landscape throughout osteoclastogenesis, we conducted Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) with BMM (D0), OC precursors day 1 (D1), OC precursor day 2 (D2), and OC (D3).

2023-01-01 | GSE212627 | GEO

SUV39H1 Maintains Cancer Stem Cells in Glioblastoma [ATAC-seq]

Project description:Glioblastoma (GBM) is the deadliest brain cancer, driven in part by GBM stem cells (GSCs) that contribute to therapeutic resistance and tumor recurrence. Effective targeting and elimination of GSCs hold promise for preventing GBM recurrence and achieving potential cures. In this study, we explored the role of the epigenetic regulator SUV39H1 in GSC maintenance and GBM progression. We observed that SUV39H1 is upregulated in GBM samples compared to normal brain tissues. Single-cell RNA-seq data indicated that SUV39H1 is preferentially expressed in GSCs relative to non-stem GBM cells, possibly due to super-enhancer-mediated transcriptional activation. Knockdown of SUV39H1 in patient-derived GSCs impaired their proliferation and stemness. RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. Integrated ATAC-seq (assay for transposase-accessible chromatin followed by sequencing) and RNA-seq analyses demonstrated that targeting SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Treatment with chaetocin, a SUV39H1 inhibitor, mimicked the effects of SUV39H1 knockdown in GSCs and sensitized them to the GBM chemotherapy drug temozolomide (TMZ). In vivo studies using an intracranial patient-derived xenograft model showed that targeting SUV39H1 inhibited GSC-driven tumor formation in mice. Our findings identify SUV39H1 as a critical regulator of GSC maintenance and suggest that targeting SUV39H1 could disrupt GSCs and enhance the efficacy of existing chemotherapy, offering a promising strategy for improving GBM treatment outcomes.

2024-11-06 | GSE273013 | GEO

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