Mapping of Notch1 binding sites in a mouse immature T cell line
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE46114 | GEO | 2014/04/02
SECONDARY ACCESSION(S): PRJNA197294
REPOSITORIES: GEO
Similar Datasets
Project description:We used an immature mouse T cell line engineered to express a biotinylated form of the cleaved form of Notch1 (ICN1). ICN1-bound sites were precipitated with streptavidin-coated beads and subjected to ChIP-sequencing. Beko cells correspond to a spontaneous T lymphoma immature cell line derived from a TCRb deficient mouse. These cells were engineered to express a biotin-tagged-ICN1 and the bacterial biotin ligase BirA (Bio-ICN1) or just BirA as a control (Bio). Chromatin from both cell lines was subjected to strepatavidin-mediated precipitation and subjected to sequencing with the Illumina GAII sequencer as single end 36 base pair reads.
2014-04-02 | E-GEOD-46114 | biostudies-arrayexpress
Project description:NOTCH1 is mutationally activated in ~15% of cases of chronic lymphocytic leukaemia (CLL), but its role in B-cell development and leukemogenesis is not known. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ~50% of peripheral blood CLL cases lacking gene mutations. We identify a ‘NOTCH1 CLL gene expression signature’ in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival and signal transduction physiology. In particular, we show that MYC is a direct target of NOTCH1 via B-cell specific distal regulatory elements, thus implicating this oncogene in the pathogenesis of the disease.
2017-03-24 | GSE92701 | GEO
Project description:Transformed human esophageal keratinocyte cell line EPC2-T (EPC2-hTERT-EGFR-cyclin D1-p53R175H) cells were stimulated with or without 2.5 ng/ml recombinant human TGF-beta1 for 10 days. The above cells were subjected to treatment for 10 days with or without 0.5 µg/ml doxycycline (DOX) to activate tetracycline-inducible (tet-on) ICN1, an active form of Notch1.
2014-12-31 | GSE37994 | GEO
Project description:NOTCH1 is mutationally activated in ~15% of cases of chronic lymphocytic leukaemia (CLL), but its role in B-cell development and leukemogenesis is not known. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ~50% of peripheral blood CLL cases lacking gene mutations. We identify a ‘NOTCH1 CLL gene expression signature’ in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival and signal transduction physiology. In particular, we show that MYC is a direct target of NOTCH1 via B-cell specific distal regulatory elements, thus implicating this oncogene in the pathogenesis of the disease.
2017-03-24 | GSE92626 | GEO
Project description:Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice. Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice.
2016-07-06 | PXD001237 | Pride
Project description:The TEL-JAK2 fusion oncogene and the ICN1 activated allele of NOTCH1 are the result of specific chromosomal translocations in T cell acute lymphoblastic leukemia (T-ALL). Mouse models of these diseases (TEL-JAK2 transgenic mice; Carron C. et al. Blood (2000); a bone marrow transplantation model for ICN1-induced T-ALL) were used to compare the transcriptional program specific to each oncoprotein in mouse models of these leukemias. Tumor load was >50% leukemic cells in all selected organs.
2013-09-28 | GSE51243 | GEO
Project description:The most recurrently mutated oncogene in T-cell acute lymphoblastic leukemia (T-ALL) is NOTCH1. The core Notch complex consists of an ICN protein, a Maml cofactor, and the DNA binding factor Rbpj. The known direct cofactors of Notch appear to act nonselectively, homogeneously driving Notch gene expression functions. It is unclear whether there are direct cofactors of Notch that act selectively and heterogeneously regulate ICN. We discovered that Zmiz1, a Protein Inhibitor of Activated STAT (PIAS)-like coactivator, directly bound ICN1. In order to determine whether this interaction occured at chromatin, we performed ChIP-Seq. We identified significant overlap between ICN1, Rbpj, and Zmiz1 peaks. 75% of overlapping ICN1/Rbpj peaks overlapped with Zmiz1 (HA) peaks (273 peaks). The size of Zmiz1 (HA) peaks had moderate correlation with the size of Rbpj and ICN1 peaks. Like Rbpj and ICN1 peaks, Zmiz1 (HA) peaks were associated with activating H3K27ac, H3K4me1, and H3K4me3 chromatin marks and were devoid of repressive H3K27me3 marks. These data suggest that Zmiz1 is a selective Notch regulator. It co-binds only a subset of ICN1 and Rbpj-regulated sites.
2015-10-28 | GSE66146 | GEO
Project description:The most recurrently mutated oncogene in T-cell acute lymphoblastic leukemia (T-ALL) is NOTCH1. The core Notch complex consists of an ICN protein, a Maml cofactor, and the DNA binding factor Rbpj. The known direct cofactors of Notch appear to act nonselectively, homogeneously driving Notch gene expression functions. It is unclear whether there are direct cofactors of Notch that act selectively and heterogeneously regulate ICN. We discovered that Zmiz1, a Protein Inhibitor of Activated STAT (PIAS)-like coactivator, directly bound ICN1. In order to determine whether this interaction occured at chromatin, we performed ChIP-Seq. We identified significant overlap between ICN1, Rbpj, and Zmiz1 peaks. 75% of overlapping ICN1/Rbpj peaks overlapped with Zmiz1 (HA) peaks (273 peaks). The size of Zmiz1 (HA) peaks had moderate correlation with the size of Rbpj and ICN1 peaks. Like Rbpj and ICN1 peaks, Zmiz1 (HA) peaks were associated with activating H3K27ac, H3K4me1, and H3K4me3 chromatin marks and were devoid of repressive H3K27me3 marks. These data suggest that Zmiz1 is a selective Notch regulator. It co-binds only a subset of ICN1 and Rbpj-regulated sites. Zmiz1, ICN1, Rbpj, histone mehylation ChIP-Seq in murine T-ALL cell line
2015-10-28 | E-GEOD-66146 | biostudies-arrayexpress
Project description:The TEL-JAK2 fusion oncogene and the ICN1 activated allele of NOTCH1 are the result of specific chromosomal translocations in T cell acute lymphoblastic leukemia (T-ALL). Mouse models of these diseases (TEL-JAK2 transgenic mice; Carron C. et al. Blood (2000); a bone marrow transplantation model for ICN1-induced T-ALL) were used to compare the transcriptional program specific to each oncoprotein in mouse models of these leukemias. Tumor load was >50% leukemic cells in all selected organs. Leukemic cells were collected from the thymus of terminally-ill TEL-JAK2 leukemic mice and bone marrow of terminally-ill ICN1 leukemic mice. RNA was extracted from each sample and processed for hybridization to Affymetrix arrays.
2013-09-28 | E-GEOD-51243 | biostudies-arrayexpress
Project description:Activated NOTCH1 induces T-ALL in mice when transduced in bone marrow (BM) cells. T-ALL cells activate the calcineurin/NFAT pathway in vivo (Medyouf H. et al. Nat Med 2007 [PMID 17515895]). Through appropriate crosses, mouse ICN1-induced T-ALL were generated that include a ROSCreERT2 transgene and 2 copies of a CnB1 floxed alleles.
2014-08-09 | GSE60258 | GEO