The CBP KIX domain regulates long-term memory and circadian activity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA636822 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11909637_1.fastq.gz | Fastqsanger.gz | |||
| SRR11909637_2.fastq.gz | Fastqsanger.gz | |||
| SRR11909638_1.fastq.gz | Fastqsanger.gz | |||
| SRR11909638_2.fastq.gz | Fastqsanger.gz | |||
| SRR11909639_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. Method: We performed total RNA sequencing after training for hippocampus-dependent memory from CBP KIX/KIX and WT littermates. Results: Using an unbiased analysis of gene expression after training for hippocampus-dependent memory, we discovered dysregulation of CREB and CLOCK target genes and downregulation of circadian genes in CBPKIX/KIX mice. Conclusion: This study provides insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms.
2020-06-03 | GSE151681 | GEO
Project description:BACKGROUND:CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors potentially affecting expression of thousands of genes. Identifying specific domain functions for multi-domain proteins is essential to understand processes such as cognitive function and circadian clocks. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. RESULTS:We found that CBPKIX/KIX mice were impaired in long-term memory, but not learning acquisition or short-term memory for the Morris water maze. Using an unbiased analysis of gene expression in the dorsal hippocampus after training in the Morris water maze or contextual fear conditioning, we discovered dysregulation of CREB, CLOCK, and BMAL1 target genes and downregulation of circadian genes in CBPKIX/KIX mice. Given our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity and phase resetting in CBPKIX/KIX mice. CBPKIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark. Interestingly, CBPKIX/KIX mice displayed phase delays and advances in response to photic stimulation comparable to wildtype littermates. Thus, this work delineates site-specific regulation of the circadian clock by a multi-domain protein. CONCLUSIONS:These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms.
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Project description:EP300 and CBP are paralogous, multidomain histone acetyltransferases (HATs) that regulate gene expression by binding to and acetylating diverse proteins. With widespread effects on gene regulation, these enzymes are attractive targets for therapeutic development. Discovery efforts for chemical inhibitors typically target protein domains that are amenable to probe binding. In some cases, probes have been identified for more than one domain within a single protein, including high potency inhibitors of both the catalytic HAT domain and bromodomain (BRD) that mediate the enzymatic and protein binding (“reader”) activities of EP300/CBP. In cancer cell systems, combination inhibition of both domains is more toxic than single inhibitor alone, indicating that inhibition of individual domain functions may elicit differential effects. Thus, we hypothesized that determining the relative effects of domain-specific inhibition of EP300/CBP on tumor cell growth may elucidate exceptional-responding tumor types to one inhibitor or the other. This would permit a broader therapeutic index by enabling reduced dosing of domain-targeted inhibitors, while maintaining enhanced inhibition of cancer cell growth. Here, using high-throughput cell line-based screening, we demonstrate that targeting the HAT or BRD domains of EP300/CBP using the chemical probes A485 and CCS1477 has differential effects in select tumor types. Group 3 medulloblastoma (G3MB) cells were especially sensitive to EP300/CBP BRD inhibition, as compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, the effects of bromodomain and HAT-domain specific inhibition are distinct, with bromodomain inhibition causing rapid early disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB cells.
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Project description:The circadian clock is an endogenous oscillator that drives daily rhythms in physiology, behavior and gene expression. The underlying mechanisms of circadian timekeeping are cell-autonomous and involve interconnecting transcription-translation feedback loops. The hippocampus plays an important role in spatial memory and the conversion of short-term to long-term memory. Several studies have reported the presence of a peripheral oscillator in the hippocampus, and have highlighted the importance of circadian regulation in memory formation. In this study we performed global quantitative proteome and phosphoproteome analyses of the murine hippocampus across the circadian cycle, applying spiked-in labeled reference and high accuracy mass spectrometry.
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Project description:Activation of oncogenic gene expression from long-range enhancers is initiated by the assembly of DNA-binding transcription factors (TF), leading to recruitment of co-activators such as CBP/p300 to modify the local genomic context and facilitate RNA-Polymerase 2 (Pol2) binding. Yet, most TF-to-coactivator recruitment relationships remain unmapped. Here, studying the oncogenic fusion TF PAX3-FOXO1 (P3F) from alveolar rhabdomyosarcoma (aRMS), we show that a single cysteine in the activation domain (AD) of PAX3-FOXO1 forms a small alpha helical hook that recruits CBP/p300 to chromatin. P3F driven transcription requires both this single cysteine, and also CBP/p300. Furthermore, we discover a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in aRMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription.
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Project description:Group 3 medulloblastomatranscriptional networks collapse under domain-specific EP300/CBP inhibition.
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Project description:We have performed RNA-seq on mouse islets lacking all p300 (p300 KO), all CBP (CBP-null), and one copy of CBP and all p300 (triallelic). The data revealed that p300 and CBP regulate some distinct but largely overlapping genes in islets. This was further confirmed by GO term and transcription factor target analyses, which suggested that these coactivators regulate genes that function similarly and converge to Hnf1a pathway.
2017-12-11 | GSE101537 | GEO
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