Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer
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ABSTRACT:
PROVIDER: PRJNA1073574 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27882400_1.fastq.gz | Fastqsanger.gz | |||
| SRR27882400_2.fastq.gz | Fastqsanger.gz | |||
| SRR27882500_1.fastq.gz | Fastqsanger.gz | |||
| SRR27882500_2.fastq.gz | Fastqsanger.gz | |||
| SRR27882401_1.fastq.gz | Fastqsanger.gz |
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Project description:Prostate cancer is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CBP are key cofactors that activate enhancers through histone acetylation. Here, we identify p300/CBP-mediated multisite acetylation of the histone H2B N-terminus (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancer. p300/CBP are essential for AR and ERG transcriptional activity, and their dual degradation eliminates H2BNTac and H3K27ac marks at hyperactive enhancers more effectively than targeting either paralog or bromodomains alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancer, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists, and showed no evident toxicity. These findings position H2BNTac as a key epigenetic marker of enhancer addiction and support dual p300/CBP degradation as a promising therapy for enhancer-driven cancers.
2025-07-28 | PXD065228 | Pride
Project description:Prostate cancer is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CBP are key cofactors that activate enhancers through histone acetylation. Here, we identify p300/CBP-mediated multisite acetylation of the histone H2B N-terminus (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancer. p300/CBP are essential for AR and ERG transcriptional activity, and their dual degradation eliminates H2BNTac and H3K27ac marks at hyperactive enhancers more effectively than targeting either paralog or bromodomains alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancer, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists, and showed no evident toxicity. These findings position H2BNTac as a key epigenetic marker of enhancer addiction and support dual p300/CBP degradation as a promising therapy for enhancer-driven cancers.
2025-07-28 | PXD065292 | Pride
Project description:Prostate cancer (PCa) is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CBP are key cofactors that activate enhancers through histone acetylation. Here, we identify p300/CBP-mediated multisite acetylation of the histone H2B N-terminus (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancerPCa. p300/CBP are essential for AR and ERG transcriptional activity, and their dual degradation eliminates H2BNTac and H3K27ac marks at hyperactive enhancers, leading to stronger suppression of oncogenic transcription more effectively than targeting either paralog or bromodomains alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancerPCa, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists, and showed no evident toxicity. These findings position H2BNTac as an key epigenetic marker of enhancer addiction and establish support dual p300/CBP degradation as a promising therapeutic strategypy for enhancer-driven cancers.
2025-06-26 | GSE255132 | GEO
Project description:Prostate cancer (PCa) is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CBP are key cofactors that activate enhancers through histone acetylation. Here, we identify p300/CBP-mediated multisite acetylation of the histone H2B N-terminus (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancerPCa. p300/CBP are essential for AR and ERG transcriptional activity, and their dual degradation eliminates H2BNTac and H3K27ac marks at hyperactive enhancers, leading to stronger suppression of oncogenic transcription more effectively than targeting either paralog or bromodomains alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancerPCa, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists, and showed no evident toxicity. These findings position H2BNTac as an key epigenetic marker of enhancer addiction and establish support dual p300/CBP degradation as a promising therapeutic strategypy for enhancer-driven cancers.
2025-06-26 | GSE255131 | GEO
Project description:Prostate cancer (PCa) is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CBP are key cofactors that activate enhancers through histone acetylation. Here, we identify p300/CBP-mediated multisite acetylation of the histone H2B N-terminus (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancerPCa. p300/CBP are essential for AR and ERG transcriptional activity, and their dual degradation eliminates H2BNTac and H3K27ac marks at hyperactive enhancers, leading to stronger suppression of oncogenic transcription more effectively than targeting either paralog or bromodomains alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancerPCa, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists, and showed no evident toxicity. These findings position H2BNTac as an key epigenetic marker of enhancer addiction and establish support dual p300/CBP degradation as a promising therapeutic strategypy for enhancer-driven cancers.
2025-06-26 | GSE255133 | GEO
Project description:Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer (RNA-Seq)
| PRJNA1073579 | ENA
Project description:Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer (ChIP-Seq)
| PRJNA1073576 | ENA
Project description:Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer (ATAC-Seq)
| PRJNA1073577 | ENA
Project description:Histone acetylation is important for the activation of gene transcription but little is known about its direct ‘read/write’ mechanisms. Here, we report cryo-electron microscopy structures in which a p300/CBP multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for ‘reading’, but also interacted with the DNA minor grooves via the outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 ‘writes’ by ‘reading’ H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP ‘replicates’ histone NT acetylation within the H3-H4 tetramer to inherit epigenetic storage, and ‘transcribes’ it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.
2023-05-08 | PXD040835 | Pride
Project description:Chromatin features are widely used for genome-scale mapping of enhancers. However, discriminating active enhancers from other cis-regulatory elements, predicting enhancer strength, and identifying their target genes remains challenging. Here we establish histone H2B N-terminus multisite lysine acetylation (H2BNTac) as a genuine signature of active enhancers. H2BNTac prominently marks candidate active enhancers and a subset of promoters and discriminates them from ubiquitously active promoters. Two mechanisms afford the distinct H2BNTac specificity. (1) Unlike H3K27ac, H2BNTac is specifically catalyzed by CBP/p300. (2) H2A-H2B, but not H3-H4, are rapidly exchanged through transcription-induced nucleosome remodeling. H2BNTac-positive candidate enhancers show a high validation rate in orthogonal enhancer activity assays, and a vast majority of endogenously active enhancers are marked by H2BNTac and H3K27ac. Notably, H2BNTac intensity predicts enhancer strength and outperforms the current state-of-the-art models in predicting CBP/p300 target genes. These findings have broad implications for generating fine-grained enhancer maps and modeling CBP/p300-dependent gene regulation.
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