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Development of gene expression signatures for knockdown of synthetic lethal gene

ABSTRACT: We performed genome-wide expression profiling analysis to define the genes underlying the synthetic-lethal relationship between CBP and p300. We extracted 1,936 genes whose expression levels changed >2-fold upon p300-knockdown (KD) in CBP-KO cells, or upon CBP-KD in p300-KO cells, but not in either KD in wild-type cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE73682 | GEO | 2015/12/12

SECONDARY ACCESSION(S): PRJNA297663

REPOSITORIES: GEO

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Development of gene expression signatures for knockdown of synthetic lethal gene

Project description:We performed genome-wide expression profiling analysis to define the genes underlying the synthetic-lethal relationship between CBP and p300. We extracted 1,936 genes whose expression levels changed >2-fold upon p300-knockdown (KD) in CBP-KO cells, or upon CBP-KD in p300-KO cells, but not in either KD in wild-type cells Gene expression profile in human lung H1299, H1299 CBP KO, H1299 p300KO cells was measured at 48 hours after transfection of siNT, siCBP or sip300. Two independent experiments were performed at each time (48 hours).

2015-12-12 | E-GEOD-73682 | biostudies-arrayexpress

Neurog3-Cre p300/CBP mouse islets RNA-seq

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

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

Targeting p300/CBP axis in lethal prostate cancer

Project description:Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR co-activators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, alters the transcriptome of Prostate Cancer cell models

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Targeting p300/CBP axis in lethal prostate cancer

Project description:Targeting p300/CBP axis in lethal prostate cancer

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

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CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_Toledo]

Project description:Somatic mutations affecting CREBBP and EP300 are a hallmark of Diffuse Large B Cell Lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small molecule inhibitors of CARM1 in DLBCL and other cancers.

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CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_MEF]

2020-06-18 | GSE152666 | GEO

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [ChIP-seq]

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Targeting Dependency on a Paralog Pair of CBP/p300 against De-repression of KREMEN2 in SMARCB1-Deficient Cancers

Project description:SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex, is the causative gene of rhabdoid tumors and epithelioid sarcomas. Here, we identify a paralog pair of CBP and p300 as a synthetic lethal target in SMARCB1-deficient cancers by using a dual siRNA screening method based on the “simultaneous inhibition of a paralog pair” concept. Treatment with CBP/p300 dual inhibitors suppresses growth of cell lines and tumor xenografts derived from SMARCB1-deficient cells but not from SMARCB1-proficient cells. SMARCB1-containing SWI/SNF complexes localize with H3K27me3 and its methyltransferase EZH2 at the promotor region of the KREMEN2 locus, resulting in transcriptional downregulation of KREMEN2. By contrast, SMARCB1 deficiency leads to localization of H3K27ac, and recruitment of its acetyltransferases CBP and p300, at the KREMEN2 locus, resulting in transcriptional upregulation of KREMEN2, which cooperates with the SMARCA1 chromatin remodeling complex. Simultaneous inhibition of CBP/p300 leads to transcriptional downregulation of KREMEN2, followed by apoptosis induction via monomerization of KREMEN1 due to a failure to interact with KREMEN2, which suppresses anti-apoptotic signaling pathways. Taken together, our findings indicate that simultaneous inhibitors of CBP/p300 could be promising therapeutic agents for SMARCB1-deficient cancers.

2024-04-29 | GSE237043 | GEO

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