Enhancer Activity Requires CBP/P300 Bromodomain-Dependent Histone H3K27 Acetylation

Raisner, Ryan; Kharbanda, Samir; Jin, Lingyan; Jeng, Edwin E.; Chan, Emily; Merchant, Mark; Haverty, Peter M.; Bainer, Russell; Cheung, Tommy K.; Arnott, David; Flynn, E. Megan; Romero, F. Anthony; Magnuson, Steven; Gascoigne, Karen E.

doi:10.1016/j.celrep.2018.07.041

Cited by 268 publications

(246 citation statements)

References 21 publications

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“…Overall, and in agreement with our previous observations and others (Raisner et al 2018;Martire et al 2019), these data demonstrate that maintenance of the open chromatin state in mESCs is independent of the high levels of H3K27ac enrichment observed at these regions in wild-type mESCs.…”

Section: Results P300 Maintains Enhancer Acetylation In Mescssupporting

confidence: 93%

“…Nevertheless, this data aligns with our previous observation that a significant reduction of p300 HAT activity (i.e., H3K27ac) fails to "close" chromatin at p300 targets (Martire et al 2019). It is also supported by a recent study in which small-molecule inhibition of the CBP/p300 bromodomain reduced global H3K27ac without changing the open chromatin state (Raisner et al 2018). Taken together, these data suggest that neither the HAT activity of p300 nor more fundamentally its presence is required to maintain open chromatin at regulatory regions.…”

Section: Discussionsupporting

confidence: 91%

“…Although p300 and CBP function is described at both promoters and enhancers (Dancy and Cole 2015) our findings indicate that enhancers are the principal sites affected by reduced levels of p300. This observation is in agreement with patterns of H3K27ac loss after treatment with CBP/p300 bromodomain inhibitor (Raisner et al 2018). Previous studies have interpreted results such as these as an indication that CBP/p300 play a more important role at enhancers.…”

Section: Discussionsupporting

confidence: 90%

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Differential contribution of p300 and CBP to regulatory elements in mESCs

Matarazzo

Sundaresan

Banaszynski³

2019

Preprint

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The transcription coactivators CREB binding protein (CBP) and p300 are highly homologous acetyltransferases that mediate histone 3 lysine 27 acetylation (H3K27ac) at regulatory elements such as enhancers and promoters. Although in most cases, CBP and p300 are considered to be functionally identical, both proteins are indispensable for development and there is evidence of tissue-specific nonredundancy. However, characterization of chromatin and transcription states regulated by each protein is lacking. In this study we analyze the individual contribution of p300 and CBP to the H3K27ac landscape, chromatin accessibility, and transcription in mouse embryonic stem cells (mESC). We demonstrate that p300 is responsible for the majority of H3K27ac in mESCs and that loss of acetylation in p300-depleted mESCs is more pronounced at enhancers compared to promoters. While loss of either CBP or p300 has little effect on the open state of chromatin, we observe that distinct gene sets are transcriptionally dysregulated upon depletion of p300 or CBP. Transcriptional dysregulation is generally correlated with dysregulation of promoter acetylation upon depletion of p300 (but not CBP) and appears to be relatively independent of dysregulated enhancer acetylation. Interestingly, both our transcriptional and genomic analyses demonstrate that targets of the p53 pathway are stabilized upon deletion of p300, suggesting that this pathway is highly prioritized when p300 levels are limited.3

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Section: Results P300 Maintains Enhancer Acetylation In Mescssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

See 1 more Smart Citation

Differential contribution of p300 and CBP to regulatory elements in mESCs

Matarazzo

Sundaresan

Banaszynski³

2019

Preprint

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“…Surprisingly, the effects of p300 and H3K27ac are seen rapidly, as soon as 5min after dexamethasone treatment. As expected, H3K27ac deposition is temporally lagged behind its canonical acetyl-transferase p300 [29,60,51]. Additionally, the enhancer marks H3K4me1 and H3K4me2 show strong enrichment of GR by 30min but the promoter mark H3K4me3 shows only modest enrichment, further supporting the finding that GR binds primarily at enhancers [44] (Supp.…”

Section: Tfea Work On Numerous Regulatory Data Types Including Chip supporting

confidence: 80%

Transcription factor enrichment analysis (TFEA): Quantifying the activity of hundreds of transcription factors from a single experiment

Rubin

Stanley

Sigauke

et al. 2020

Preprint

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Detecting differential activation of transcription factors (TFs) in response to perturbation provides insight into cellular processes. Transcription Factor Enrichment Analysis (TFEA) is a robust and reliable computational method that detects differential activity of hundreds of TFs given any set of perturbation data. TFEA draws inspiration from GSEA and detects positional motif enrichment within a list of ranked regions of interest (ROIs). As ROIs are typically inferred from the data, we also introduce muMerge, a statistically principled method of generating a consensus list of ROIs from multiple replicates and conditions. TFEA is broadly applicable to data that informs on transcriptional regulation including nascent (eg. PRO-Seq), CAGE, ChIP-Seq, and accessibility (e.g. ATAC-Seq). TFEA not only identifies the key regulators responding to a perturbation, but also temporally unravels regulatory networks with time series data. Consequently, TFEA serves as a hypothesis-generating tool that provides an easy, rigorous, and cost-effective means to broadly assess TF activity yielding new biological insights.

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“…In addition, efficient, transient histone acetylation and deacetylation at the targeted enhancer and promoter regions were achieved by using dCas9-P300 (Hilton et al 2015) and dCas9-HDAC3 (Kwon et al 2017), respectively. P300 is a histone acetyltransferase that acts as a co-activator by mediating acetylation of H3K27ac on the enhancer region (Raisner et al 2018). In contrast, HDAC3 functions as a corepressor by deacetylating the H3K27ac on enhancer elements (Hatzi et al 2013).…”

Section: Crispr-based Epigenome Editing and Transcriptional Modulatiomentioning

confidence: 99%

In vivo epigenome editing and transcriptional modulation using CRISPR technology

Lau

Suh

2018

Transgenic Res

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The rapid advancement of CRISPR technology has enabled targeted epigenome editing and transcriptional modulation in the native chromatin context. However, only a few studies have reported the successful editing of the epigenome in adult animals in contrast to the rapidly growing number of in vivo genome editing over the past few years. In this review, we discuss the challenges facing in vivo epigenome editing and new strategies to overcome the huddles. The biggest challenge has been the difficulty in packaging dCas9 fusion proteins required for manipulation of epigenome into the adeno-associated virus (AAV) delivery vehicle. We review the strategies to address the AAV packaging issue, including small dCas9 orthologues, truncated dCas9 mutants, a split-dCas9 system, and potent truncated effector domains. We discuss the dCas9 conjugation strategies to recruit endogenous chromatin modifiers and remodelers to specific genomic loci, and recently developed methods to recruit multiple copies of the dCas9 fusion protein, or to simultaneous express multiple gRNAs for robust epigenome editing or synergistic transcriptional modulation. The use of Cre-inducible dCas9-expressing mice or a genetic cross between dCas9- and sgRNA-expressing flies has also helped overcome the transgene delivery issue. We provide perspective on how a combination use of these strategies can facilitate in vivo epigenome editing and transcriptional modulation.

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Enhancer Activity Requires CBP/P300 Bromodomain-Dependent Histone H3K27 Acetylation

Cited by 268 publications

References 21 publications

Differential contribution of p300 and CBP to regulatory elements in mESCs

Differential contribution of p300 and CBP to regulatory elements in mESCs

Transcription factor enrichment analysis (TFEA): Quantifying the activity of hundreds of transcription factors from a single experiment

In vivo epigenome editing and transcriptional modulation using CRISPR technology

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