A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-directed Cell Death [ChIP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1213717 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32061737_1.fastq.gz | Fastqsanger.gz | |||
| SRR32061737_2.fastq.gz | Fastqsanger.gz | |||
| SRR32061738_1.fastq.gz | Fastqsanger.gz | |||
| SRR32061738_2.fastq.gz | Fastqsanger.gz | |||
| SRR32061739_1.fastq.gz | Fastqsanger.gz |
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Project description:A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-directed Cell Death [CUT&RUN]
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Project description:Lysine acetyltransferases (KATs) such as p300 and CBP regulate gene networks in healthy and malignant cells by scaffolding transcriptional machinery and by acetylating chromatin and transcription factors (TFs). In certain cancers including diffuse large B cell lymphomas, they contribute to tumor suppression and are therapeutic vulnerabilities when deregulated. Inhibitors and degraders of KATs are limited by potential toxicity associated with targeting these essential proteins. We introduce KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity), bivalent molecules that redirect the KAT and co-activating activity of p300 and CBP towards programmed cell death signaling repressed by the oncogenic TF BCL6. The lead KAT-TCIP molecule kills lymphoma cells at ~0.8 nM by redistributing chromatin acetylation, activating the pro-apoptotic protein PUMA, and repressing c-MYC. Analysis of the ternary co-crystal structure containing p300 and BCL6 reveals fortuitous interactions that drive the potency and specificity of KAT-TCIPs and sets a precedent for KAT-targeting induced proximity therapeutics.
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Project description:Lysine acetyltransferases (KATs) such as p300 and CBP regulate gene networks in healthy and malignant cells by scaffolding transcriptional machinery and by acetylating chromatin and transcription factors (TFs). In certain cancers including diffuse large B cell lymphomas, they contribute to tumor suppression and are therapeutic vulnerabilities when deregulated. Inhibitors and degraders of KATs are limited by potential toxicity associated with targeting these essential proteins. We introduce KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity), bivalent molecules that redirect the KAT and co-activating activity of p300 and CBP towards programmed cell death signaling repressed by the oncogenic TF BCL6. The lead KAT-TCIP molecule kills lymphoma cells at ~0.8 nM by redistributing chromatin acetylation, activating the pro-apoptotic protein PUMA, and repressing c-MYC. Analysis of the ternary co-crystal structure containing p300 and BCL6 reveals fortuitous interactions that drive the potency and specificity of KAT-TCIPs and sets a precedent for KAT-targeting induced proximity therapeutics.
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Project description:Lysine acetyltransferases (KATs) such as p300 and CBP regulate gene networks in healthy and malignant cells by scaffolding transcriptional machinery and by acetylating chromatin and transcription factors (TFs). In certain cancers including diffuse large B cell lymphomas, they contribute to tumor suppression and are therapeutic vulnerabilities when deregulated. Inhibitors and degraders of KATs are limited by potential toxicity associated with targeting these essential proteins. We introduce KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity), bivalent molecules that redirect the KAT and co-activating activity of p300 and CBP towards programmed cell death signaling repressed by the oncogenic TF BCL6. The lead KAT-TCIP molecule kills lymphoma cells at ~0.8 nM by redistributing chromatin acetylation, activating the pro-apoptotic protein PUMA, and repressing c-MYC. Analysis of the ternary co-crystal structure containing p300 and BCL6 reveals fortuitous interactions that drive the potency and specificity of KAT-TCIPs and sets a precedent for KAT-targeting induced proximity therapeutics.
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Project description:Histone acetyltransferases (HAT) assemble into multisubunit complexes in order to target distinct lysine residues on nucleosomal histones. Here, we characterize native HAT complexes assembled by the BRPF-family of scaffold proteins. Their PHD-ZnKnuckle-PHD domain is essential for binding chromatin and restricted to unmethylated H3K4, a specificity that is reversed by the associated ING subunit. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as catalytic acetyltransferase subunit. Interestingly, while the previously reported HBO1 complexes containing JADE scaffold proteins target histone H4, the HBO1-BRPF1 complex acetylates only H3 in chromatin. We mapped a small region at the N-terminus of scaffold proteins responsible for histone tail selection on chromatin. Thus, alternate choice of subunits associated with HBO1 can switch its specificity from H4 to H3 tails, highlighting a crucial new role of associated subunits within HAT complexes, previously thought to be intrinsic to the catalytic subunit. Genome-wide mapping of MYST acetyltransferases subunits and H3K4me3 histone mark in RKO cells.
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