Histone posttranslational modifications and cell fate determination: Lens induction requires the lysine acetyltransferases CBP and p300
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE49219 | GEO | 2013/09/23
SECONDARY ACCESSION(S): PRJNA213302
REPOSITORIES: GEO
Similar Datasets
Project description:Lens induction is a classical embryologic model to study cell fate determination. It has been proposed earlier that specific changes in core histone modifications accompany the process of cell fate specification and determination. The lysine acetyltransferases CBP and p300 function as principal enzymes that modify core histones to facilitate specific gene expression. Herein, we performed conditional inactivation of both CBP and p300 in the ectodermal cells that give rise to the lens placode. Inactivation of both CBP and p300 resulted in the dramatic discontinuation of all aspects of lens specification and organogenesis, resulting in aphakia. The CBP/p300(-/-) ectodermal cells are viable and not prone to apoptosis. These cells showed reduced expression of Six3 and Sox2, while expression of Pax6 was not upregulated, indicating discontinuation of lens induction. Consequently, expression of αB- and αA-crystallins was not initiated. Mutant ectoderm exhibited markedly reduced levels of histone H3 K18 and K27 acetylation, subtly increased H3 K27me3 and unaltered overall levels of H3 K9ac and H3 K4me3. Our data demonstrate that CBP and p300 are required to establish lens cell-type identity during lens induction, and suggest that posttranslational histone modifications are integral to normal cell fate determination in the mammalian lens.
| S-EPMC3905850 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-09-23 | E-GEOD-49219 | biostudies-arrayexpress
Project description:The histone acetyltransferases CBP and p300, often referred to as CBP/p300 due to their sequence homology and functional overlap and co-operation, are emerging as critical drivers of oncogenesis in the past several years. CBP/p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers and super-enhancers, thereby activating gene transcription. While earlier studies indicate that CBP/p300 deletion/loss can promote tumorigenesis, CBP/p300 have more recently been shown to be over-expressed in cancer cells and drug-resistant cancer cells, activate oncogene transcription and induce cancer cell proliferation, survival, tumorigenesis, metastasis, immune evasion and drug-resistance. Small molecule CBP/p300 histone acetyltransferase inhibitors, bromodomain inhibitors, CBP/p300 and BET bromodomain dual inhibitors and p300 protein degraders have recently been discovered. The CBP/p300 inhibitors and degraders reduce H3K27ac, down-regulate oncogene transcription, induce cancer cell growth inhibition and cell death, activate immune response, overcome drug resistance and suppress tumor progression in vivo. In addition, CBP/p300 inhibitors enhance the anticancer efficacy of chemotherapy, radiotherapy and epigenetic anticancer agents, including BET bromodomain inhibitors; and the combination therapies exert substantial anticancer effects in mouse models of human cancers including drug-resistant cancers. Currently, two CBP/p300 inhibitors are under clinical evaluation in patients with advanced and drug-resistant solid tumors or hematological malignancies. In summary, CBP/p300 have recently been identified as critical tumorigenic drivers, and CBP/p300 inhibitors and protein degraders are emerging as promising novel anticancer agents for clinical translation.
| S-EPMC9274749 | biostudies-literature
Project description:Tumor surveillance of natural killer (NK) cells is mediated by the cytotoxicity receptor natural-killer group 2 member D (NKG2D). Ligands for NKG2D are generally not expressed on healthy cells, but induced on the surface of malignant cells. To date, NKG2D ligand (NKG2D-L) induction was mainly described to depend on the activation of the DNA damage response, although the molecular mechanisms that regulate NKG2D-L expression remain largely unknown. Here, we show that the acetyltransferases CBP (CREB-binding protein) and p300 play a crucial role in the regulation of NKG2D-L on tumor cells. Loss of CBP/p300 decreased the basal cell surface expression of human ligands and reduced the upregulation of MICA/B and ULBP2 in response to histone deacetylase inhibitors or DNA damage. Furthermore, CBP/P300 deficiency abrogated the sensitivity of stressed cells to NK cell-mediated killing. CBP/p300 were also identified as major regulators of mouse NKG2D ligand RAE-1 in vitro and in vivo using the Eμ-Myc lymphoma model. Mechanistically, we observed an enhanced activation of the CBP/p300 binding transcription factor CREB (cAMP response element-binding protein) correlating to the NKG2D-L upregulation. Moreover, increased binding of CREB and CBP/p300 to NKG2D-L promoters and elevated histone acetylation were detectable. This study provides strong evidence for a major role of CBP and p300 in orchestrating NKG2D-L induction and consequently immunosurveillance of tumors in mice and humans. These findings might help to develop novel immunotherapeutic approaches against cancer.
| S-EPMC5318661 | biostudies-literature
Project description:p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.
| S-EPMC8392731 | biostudies-literature
Project description:The enhancer factors CBP/p300 maintain gene expression programs through lysine acetylation of chromatin and transcriptional regulators and by scaffolding functions mediated by several protein-protein interaction domains. We have designed dCBP-1, a compound that induces degradation of CBP/p300, and profiled its activity inducing global proteome changes in HAP1 and MM1S cells. The proteome changes were mapped using multiplexed quantitative proteomics (TMT11) and applying the SPS-MS3 method on either an Orbitrap Fusion or an Orbitrap Lumos Fusion mass spectrometer. The proteome was mapped 3 hours and 6 hours upon drug treatment. Samples were covered over two TMT sets for both time points. Samples for the 3 hours time points (HAP1 and MM1S) were analyzed using a total of 48 fractions on an Orbitrap Lumos mass spectrometer. Samples for the 6 hours time point (MM1S) were analyzed using a total of 20 fractions on an Orbitrap Fusion mass spectrometer. Samples were analyzed in three replicates (rep1-rep3). Pooled tryptic digests were used as bridge channels to compare proteome profiles from the two TMT sets mapped per time point.
Samples were labeled as described in the following:
3 hours:
HAP1_DMSO_3h_rep1 (Ott_3hours_TMT1_129c);
HAP1_DMSO_3h_rep2 (Ott_3hours_TMT1_130n);
HAP1_DMSO_3h_rep3 (Ott_3hours_TMT1_130c);
HAP1_dCBP1_3h_rep1 (Ott_3hours_TMT2_129c);
HAP1_dCBP1_3h_rep2 (Ott_3hours_TMT2_130n);
HAP1_dCBP1_3h_rep3 (Ott_3hours_TMT2_130c);
MM1S_DMSO_3h_rep1 (Ott_3hours_TMT1_126);
MM1S_DMSO_3h_rep2 (Ott_3hours_TMT1_127n);
MM1S_DMSO_3h_rep3 (Ott_3hours_TMT1_127c);
MM1S_dCBP1_3h_rep1 (Ott_3hours_TMT1_128n);
MM1S_dCBP1_3h_rep2 (Ott_3hours_TMT1_128c);
MM1S_dCBP1_3h_rep3 (Ott_3hours_TMT1_129n);
Bridge channels (Ott_3hours_TMT1 and TMT2, 131n).
6 hours:
TMT1_128c (Ott_6hours_TMT1_128c);
TMT2_126 (Ott_6hours_TMT2_126);
TMT2_129c (Ott_6hours_TMT2_129c);
TMT1_129n (Ott_6hours_TMT1_129n);
TMT2_127n (Ott_6hours_TMT2_127n);
TMT2_130n (Ott_6hours_TMT2_130n);
Bridge channels (Ott_6hours_TMT1 and TMT2, 131c).
2020-11-15 | MSV000086457 | MassIVE
Project description:Acetylation within the globular core domain of histone H3 on lysine 56 (H3K56) has recently been shown to have a critical role in packaging DNA into chromatin following DNA replication and repair in budding yeast. However, the function or occurrence of this specific histone mark has not been studied in multicellular eukaryotes, mainly because the Rtt109 enzyme that is known to mediate acetylation of H3K56 (H3K56ac) is fungal-specific. Here we demonstrate that the histone acetyl transferase CBP (also known as Nejire) in flies and CBP and p300 (Ep300) in humans acetylate H3K56, whereas Drosophila Sir2 and human SIRT1 and SIRT2 deacetylate H3K56ac. The histone chaperones ASF1A in humans and Asf1 in Drosophila are required for acetylation of H3K56 in vivo, whereas the histone chaperone CAF-1 (chromatin assembly factor 1) in humans and Caf1 in Drosophila are required for the incorporation of histones bearing this mark into chromatin. We show that, in response to DNA damage, histones bearing acetylated K56 are assembled into chromatin in Drosophila and human cells, forming foci that colocalize with sites of DNA repair. Furthermore, acetylation of H3K56 is increased in multiple types of cancer, correlating with increased levels of ASF1A in these tumours. Our identification of multiple proteins regulating the levels of H3K56 acetylation in metazoans will allow future studies of this critical and unique histone modification that couples chromatin assembly to DNA synthesis, cell proliferation and cancer.
| S-EPMC2756583 | biostudies-literature
Project description:p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to A-485, which exhibits potent cell activity, low clearance, and high oral bioavailability.
| S-EPMC5767893 | biostudies-literature
Project description:Lysine acetylation has emerged as a major posttranslational modification for histones. Crossregulation between this and other modifications is crucial in modulating chromatin-based transcriptional control and shaping inheritable epigenetic programs. In addition to histones, many other nuclear proteins and various cytoplasmic regulators are subject to lysine acetylation. This review focuses on recent findings pertinent to acetylation of nonhistone proteins and emphasizes how this modification might crosstalk with phosphorylation, methylation, ubiquitination, sumoylation, and others to form code-like multisite modification programs for dynamic control of cellular signaling under diverse conditions.
| S-EPMC2551738 | biostudies-literature
Project description:Acetylation of histone lysine residues by histone acetyltransferase (HAT) p300 and its paralog CBP play important roles in gene regulation in health and diseases. The HAT domain of p300/CBP has been found to be a potential drug target for cancer. Compound screening followed by structure-activity relationship studies yielded a novel series of 1,4-pyrazine-containing inhibitors of p300/CBP HAT with their IC50s as low as 1.4 μM. Enzyme kinetics and other studies support the most potent compound 29 is a competitive inhibitor of p300 HAT against the substrate histone. It exhibited a high selectivity for p300 and CBP, with negligible activity on other classes of HATs in human. Compound 29 inhibited cellular acetylation of several histone lysine residues and showed strong activity against proliferation of a panel of solid and blood cancer cells. These results indicate it is a novel pharmacological lead for drug development targeting these cancers as well as a useful chemical probe for biological studies of p300/CBP.
| S-EPMC9165588 | biostudies-literature