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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells

ABSTRACT: This SuperSeries is composed of the following subset Series: GSE25265: Genome-wide analysis of the binding pattern of the transcriptional co-activator Cbp. GSE25268: The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Wai-In Chan

PROVIDER: E-GEOD-25274 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells.

Chan Wai-In WI Hannah Rebecca L RL Dawson Mark A MA Pridans Clare C Foster Donna D Joshi Anagha A Göttgens Berthold B Van Deursen Jan M JM Huntly Brian J P BJ

Molecular and cellular biology 20111017 24

The transcriptional coactivator Cbp plays an important role in a wide range of cellular processes, including proliferation, differentiation, and apoptosis. Although studies have shown its requirement for hematopoietic stem cell (HSC) development, its role in adult HSC maintenance, as well as the cellular and molecular mechanisms underlying Cbp function, is not clear. Here, we demonstrate a gradual loss of phenotypic HSCs and differentiation defects following conditional ablation of Cbp during ad ...[more]

PMID: 22006020

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Genome-wide analysis of the binding pattern of the transcriptional co-activator Cbp.

Project description:The transcriptional coactivator Cbp is critical for hematopoietic stem cell (HSC) development. However, its role in adult HSC and the mechanistic detail of Cbp control of HSC function remain unknown. Using conditional deletion of Cbp in the adult HSC compartment, we demonstrate an altered balance between differentiation and self-renewal with gradual loss of phenotypic HSC, differentiation defects in lower compartments and the development of myeloid malignancies. In addition, we demonstrate that Cbp -/- HSCs reconstitute hematopoiesis with lower efficiency than their wild type counterparts and readily exhaust over time when placed under the replicative stress of serial transplantation. Furthermore, we demonstrate abnormal cell cycle (re)entry and apoptosis in HSC which, with preferential differentiation, also contribute to stem cell exhaustion. Finally we demonstrate global transcriptional abnormalities predicted to alter cell cycle control, balanced differentiation and HSC function upon Cbp deletion and link Cbp to a critical HSC transcriptional regulatory network through genome-wide analysis of Cbp binding. 1 sample (Cbp) and 1 control, all prepared from a hematopoietic progenitor/stem cell line (BM-HPC)

2011-12-15 | E-GEOD-25265 | biostudies-arrayexpress

Gene expression analysis of Cbp deficient LSK cells

Project description:The transcriptional coactivator Cbp is critical for hematopoietic stem cell (HSC) development. However, its role in adult HSC and the mechanistic detail of Cbp control of HSC function remains unknown. Using conditional deletion of Cbp in the adult HSC compartment, we demonstrate an altered balance between differentiation and self-renewal with gradual loss of phenotypic HSC, differentiation defects in lower compartments and the development of myeloid malignancies. In addition, we demonstrate that Cbp -/- HSCs reconstitute hematopoiesis with lower efficiency than their wild type counterparts and readily exhaust over time when placed under the replicative stress of serial transplantation. Furthermore, we demonstrate abnormal cell cycle (re)entry and apoptosis in HSC which, with preferential differentiation, also contribute to stem cell exhaustion. Finally we demonstrate global transcriptional abnormalities predicted to alter cell cycle control, balanced differentiation and HSC function upon Cbp deletion and link Cbp to a critical HSC transcriptional regulatory network through genome-wide analysis of Cbp binding. Genome-wide gene expression analysis of LSK population after Cbp deletion. The LSK population of bone marrow is enriched for hematopoietic stem cells. Total RNA was extracted from flow-sorted LSK population of bone marrow, 4 weeks after pIpC induced deletion of Cbp. 2 replicates for Cbp wt control, 2 replicates for Cbp Mx.

2011-12-15 | E-GEOD-25268 | biostudies-arrayexpress

CBP occupancy in Drosophila S2 cells

Project description:CREB-binding protein (CBP, also known as nejire) is a transcriptional co-activator that is conserved in metazoans. We have generated CBP ChIP-seq data from Drosophila S2 cells and compared it to modENCODE data. This shows that CBP is bound at genomic sites with a wide range of functions. As expected, we find that CBP is bound at active promoters and enhancers. In addition, we find that the strongest CBP sites in the genome are found at Polycomb Response Elements embedded in histone H3 lysine 27 trimethylated (H3K27me3) chromatin, where they correlate with binding of the Pho repressive complex. Interestingly, we find that CBP also binds to most insulators in the genome. At a subset of these, CBP may regulate insulating activity, measured as the ability to prevent repressive H3K27 methylation from spreading into adjacent chromatin. ChIP seq in Drosophila S2 cells using two different antibodies against CBP (nejire), one raised in rabbit against amino acids 2540-3190 (CBP rb), and one raised in guinea-pig against amino acids 1-178 (CBP gp)

2015-11-06 | E-GEOD-64464 | biostudies-arrayexpress

Dorsal dependent CBP binding on a genome wide scale

Project description:We find a high concordance between the binding of the Drosophila transcription factor Dorsal and the co-activator CBP during early embryogenesis. This relationship was furter examined by comparing CBP distribution in Drosophila embryos derived from wt and mutant flies lacking intranuclear Dorsal (gd7). Our data suggests a specific involvemet of CBP in initiating early dorsoventral patterning, but not in anterioposterior. CBP ChIP seq of 2-4 hours old Drosophila embryos derived from w1118 (wild-type) or gd7 homozygous mutant mothers

2012-06-28 | E-GEOD-34221 | biostudies-arrayexpress

CREBBP (CBP) ChIP-seq in wild type and CBP null MEFs +/- dipyridyl

Project description:Genome-wide distribution of histone H3K18 and H3K27 acetyltransferases, Crebbp (CBP) and Ep300 (p300), is used to map enhancers and promoters, but whether these elements functionally require CBP/p300 remains largely uncertain. We investigated this relationship by comparing genomic CBP recruitment with gene expression in wild type and CBP/p300 double-knockout fibroblasts. ChIP-seq revealed nearby CBP recruitment for 20 percent of constitutively expressed genes, but surprisingly, three-quarters of these were unaffected or slightly activated by CBP/p300 deletion. Computationally defined enhancer-promoter-units (EPUs) having a CBP peak within two kilobases of the enhancer-like element provided better predictive value, with CBP/p300 deletion attenuating expression of 40 percent of such EPU assigned constitutively expressed genes. We next examined signaling-responsive (Hypoxia Inducible Factor) gene expression and CBP recruitment, and found that 97 percent of inducible genes were within 50 kilobases of an inducible CBP peak, and 70 percent of these required CBP/p300 for full inducible expression. Unexpectedly however, most inducible CBP peaks occurred near signal-nonresponsive genes. eight samples total; Two wild type and two CBP null primary mouse embryonic fibroblast (MEF) lines, each treated with 100uM 2,2-dipyridyl or ethanol vehicle for 2 hours

2014-09-29 | E-GEOD-54453 | biostudies-arrayexpress

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

DBC1 regulates p53 stability via inhibition of CBP-dependent p53 polyubiquitination

Project description:The control of p53 protein stability is critical to its tumor suppressor functions. The CREB Binding Protein (CBP) transcriptional coactivator co-operates with MDM2 to maintain normally low physiologic p53 levels in cells via an exclusively cytoplasmic ‘E4’ polyubiquitination activity. Utilizing mass spectrometry to identify nuclear and cytoplasmic CBP interacting proteins that regulate compartmentalized CBP E4 activity, we identified Deleted in Breast Cancer 1 (DBC1) as a stoichiometric CBP-interacting protein that negatively regulates CBP–dependent p53 polyubiquitination, stabilizes p53, and augments p53-dependent apoptosis. TCGA analysis demonstrated that solid tumors often retain wild type p53 alleles in conjunction with DBC1 loss, supporting the hypothesis that DBC1 is selected for disruption during carcinogenesis as a surrogate for p53 functional loss. As DBC1 maintains p53 stability in the nucleus where p53 exerts its tumor suppressive transcriptional function, replacement of DBC1 functionality in DBC1-deleted tumors might also enhance p53 function and chemosensitivity for therapeutic benefit.

2019-11-13 | PXD012673 | Pride

Definition of aberrant MYB CBP/P300 complex in AML

Project description:Dysregulated gene expression is one of the most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of the MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300-mediated co-activation of a distinct set of transcriptional factor complexes that are aberrantly assembled with MYB in AML cells. This therapeutic remodeling is accompanied by dynamic redistribution of CBP/P300 complexes to genes that control cellular differentiation and growth. Thus, aberrantly organized transcription factor complexes control convergent gene expression programs in AML cells. These findings establish a compelling strategy for pharmacologic reprogramming of oncogenic gene expression that supports its targeting for leukemias and other human cancers caused by dysregulated gene control.

2020-12-17 | PXD019708 | Pride

CBP is required for environmental enrichment-induced neurogenesis and cognitive enhancement.

Project description:The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CBP, a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioral adaptations to environmental enrichment (EE). Morphological and behavioral analyses demonstrated that EE ameliorates deficits associated to CBP-deficiency. However, CBP-deficient mice also showed a strong defect in environment-induced neurogenesis and impaired EE-enhanced spatial navigation and patter separation ability. These defects correlated with an attenuation of the transcriptional program induced in response to EE and with deficits in histone acetylation at the promoters of EE-regulated, neurogenesis-related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment-induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics. To identify those genes whose expression was altered in the hippocampus of cbp heterozygous mice both under basal conditions and after 2 weeks of exposure to environmental enrichment, we performed a gene profiling analysis of hippocampal tissue using high-density oligonucleotide microarrays. We obtained quintuplicate (standard housing) and triplicate (environmental enrichment) samples containing total RNA from the hippocampi of four 3-month old females of either genotype (in total 32 cbp+/- mice and 32 wild type littermates were used in the experiment).

2011-08-29 | E-GEOD-30880 | biostudies-arrayexpress

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2010-08-12 | E-GEOD-23556 | biostudies-arrayexpress

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