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Epigenetic correction of defective plasticity in a tauopathy mouse model with an acetyltransferase activator [RNA-Seq]

ABSTRACT: In the adult brain, histone acetylation is associated with activity-regulated transcriptional changes that are required for synaptic plasticity and memory. These processes are dismantled in neurodegenerative diseases. Here, we demonstrate that synaptic plasticity and memory deficiencies can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small molecule activator of CBP/p300 histone acetyltransferases (HAT). CSP-TTK21 normalized the H2B acetylation levels in many genes, including a series of super-enhancer –regulated genes, associated with plasticity and neuronal function in resting tauopathic mice. CSP-TTK21 re-established part of the learning-induced hippocampal transcriptome, including the induction of immediate early genes and memory-related genes, and the down-regulation of neuronal identity genes that bear super-enhancers. This study is the first to provide in vivo proof-of-concept evidence that direct activation of CBP/p300 HAT efficiently and selectively reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated to Alzheimer’s disease lesions in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE103359 | GEO | 2018/11/05

REPOSITORIES: GEO

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Epigenetic correction of defective plasticity in a tauopathy mouse model with an acetyltransferase activator [ChIP-Seq]

Project description:In the adult brain, histone acetylation is associated with activity-regulated transcriptional changes that are required for synaptic plasticity and memory. These processes are dismantled in neurodegenerative diseases. Here, we demonstrate that synaptic plasticity and memory deficiencies can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small molecule activator of CBP/p300 histone acetyltransferases (HAT). CSP-TTK21 normalized the H2B acetylation levels in many genes, including a series of super-enhancer –regulated genes, associated with plasticity and neuronal function in resting tauopathic mice. CSP-TTK21 re-established part of the learning-induced hippocampal transcriptome, including the induction of immediate early genes and memory-related genes, and the down-regulation of neuronal identity genes that bear super-enhancers. This study is the first to provide in vivo proof-of-concept evidence that direct activation of CBP/p300 HAT efficiently and selectively reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated to Alzheimer’s disease lesions in mice.

2018-11-05 | GSE103358 | GEO

HOXB13 epigenome in castration-resistant prostate cancer

Project description:Treatment induced-resistance of CRPC is an imminent undesirable outcome in patients. Tissue and lineage-specific super-enhancers (SEs) determine cell fate and plasticity during development and disease respectively. However, the identity and function of CRPC-specific SEs (CSEs) regulated genes is unknown. Herein we report the lysine 13 acetylation of the prostate-enriched transcription factor HOXB13 (acK13-HOXB13) mediated by the histone acetyl transferase (HAT) CBP/p300 as a critical mechanism of CSE establishment. Mechanistically, acK13-HOXB13 establishes the CRPC enhanceosome comprising chromatin remodeling bromo-domain proteins SMARCA2/BAZ2B and the HAT p300/CBP which enable histone and non-histone protein acetylation at CSEs. Such CSEs sprout at tyrosine kinase genes encoding ACK1/TNK2, VEGFA, and ANGPT2/ANGPTL3 to increase pathogenic output in primary human tumors. These tyrosine kinase mediated signaling cascades establish robust networks to conduce growth, survival and androgen-bypass. Consistently, the loss of function acK13-HOXB13 mutants show significant reduction of proliferation, spheroid formation, and xenograft tumor growth that correlates with the high sensitivity to the AR-antagonist Enzalutamide. Targeting HOXB13 acetylation mediated CRPC-SE establishment at critical tyrosine kinase genes could therefore have significant clinical implications in preventing PC recurrence.

2022-09-22 | GSE169132 | GEO

RNA binds to a CBP regulatory motif to stimulate histone acetylation and transcription

Project description:CBP/p300 are transcription co-activators whose binding is a signature of enhancers, cis-regulatory elements that control patterns of gene expression in multicellular organisms. Active enhancers produce bi-directional enhancer RNAs (eRNAs) and display CBP/p300 dependent histone acetylation. Here, we demonstrate that CBP binds directly to RNAs in vivo and in vitro. RNAs bound to CBP in vivo include a large number of eRNAs. Using steady-state histone acetyltransferase (HAT) assays we show that an RNA binding region in the HAT domain of CBP—a regulatory motif unique to CBP/p300—allows RNA to stimulate CBP’s HAT activity. At enhancers where CBP interacts with eRNAs, stimulation manifests in RNA-dependent changes in the histone acetylation mediated by CBP, such as H3K27ac, and by corresponding changes in gene expression. By interacting directly with CBP, eRNAs contribute to the unique chromatin structure at active enhancers, which in turn is required for regulation of target genes.

2017-01-12 | GSE75684 | GEO

Regulation of p300 acetyltransferase activity by the TAZ2 domain [ATAC-seq]

Project description:The E1A binding protein P300 (EP300, also known as p300, lysine acetyltransferase 3B or KAT3B) and its close paralogue CREB-binding protein (CREBBP, aka CBP or KAT3A) possess intrinsic histone acetyltransferase (HAT) activity that can act on both histone and non-histone proteins. P300 and CBP are composed of multiple conserved protein domains, many of which are in proximity to the HAT domain modulating its catalytic activity. Here we show that the TAZ2 domain regulates the intrinsic catalytic activity of p300 in vitro and histone acetylation and chromatin accessibility in cells. Our study extends the knowledge of p300 self-regulation and provides new therapeutic stratagies for human cancers with corresponding p300/CBP mutations.

2023-08-07 | GSE193647 | GEO

Regulation of p300 acetyltransferase activity by the TAZ2 domain [ChIP-seq]

2023-08-07 | GSE193646 | GEO

Regulation of p300 acetyltransferase activity by the TAZ2 domain [RNA-seq]

2023-08-07 | GSE193645 | GEO

Enhancers are Activated by p300/CBP Activity-Dependent PIC Assembly, RNAPII Recruitment and Pause Release [EU-Seq]

Project description:The metazoan-specific acetyltransferase p300/CBP is involved in activating signalinduced, enhancer-mediated transcription of cell-type-specific genes. However, the global kinetics and mechanisms of p300/CBP activity-dependent transcription activation remain poorly understood. We performed genome-wide, time-resolved analyses to show that enhancers and super-enhancers are dynamically activated through p300/CBP-catalyzed acetylation, deactivated by the opposing deacetylase activity, and kinetic acetylation directly contributes to maintaining cell identity at very rapid timescales. The acetyltransferase activity is dispensable for the recruitment of p300/CBP and transcription factors, but essential for promoting the recruitment of TFIID and RNAPII at virtually all enhancers and enhancer-regulated genes. This identifies pre-initiation complex assembly as a dynamically controlled step in the transcription cycle and reveals p300/CBP-catalyzed acetylation as the signal that specifically promotes transcription initiation at enhancer-regulated genes. We propose that p300/CBP activity uses a ‘recruit-and-release’ mechanism to simultaneously promote RNAPII recruitment and pause release, and thereby, enables kinetic activation of enhancer-mediated transcription.

2021-03-24 | GSE146326 | GEO

Enhancers are Activated by p300/CBP Activity-Dependent PIC Assembly, RNAPII Recruitment and Pause Release [ATAC-Seq]

2021-03-24 | GSE146325 | GEO

Enhancers are Activated by p300/CBP Activity-Dependent PIC Assembly, RNAPII Recruitment and Pause Release [ChIP-Seq]

2021-03-24 | GSE146324 | GEO

Time-resolved analysis reveals rapid dynamics and broad scope of the CBP/p300 acetylome

Project description:The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators; however, their acetylation targets, site-specific acetylation kinetics, and function in proteome regulation are incompletely understood. We combined quantitative proteomics with novel CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to show that CBP/p300 acetylates thousands of sites, including signature histone sites, as well as a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Kinetic analysis identified a subset of CBP/p300-regulated sites with very rapid (<30min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions, as well as for understanding the impact of small molecule inhibitors targeting its catalytic and bromodomain activities.

2018-06-10 | PXD005252 | Pride

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