E2f and Myc transcriptional programs and chromatin binding landscapes in the small intestines
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ABSTRACT:
PROVIDER: PRJNA242195 | ENA |
REPOSITORIES: ENA
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Project description:To explore how Myc and E2f3 might coordinate gene expression programs that drive normal cell cycles in wild type intestines and ectopic cell cycles in Rb-deficient small intestines, we compared Myc and E2f3 chromatin occupancy in these tissues.
2015-07-20 | GSE56008 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2015-07-20 | GSE56009 | GEO
Project description:Therapeutic targeting of CDK7 has proven beneficial in pre-clinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in multiple myeloma (MM) patient cells; and its selective targeting counteracts E2F activity via perturbation of the CDKs/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression increasing survival in several MM mouse models including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use.
2023-02-01 | GSE172441 | GEO
Project description:Rb and E2F are thought to play antagonistic roles in celll proliferation. However, this model is based mostly from in vitro cell culture systems. We used small intestines to test this model in vivo. We found that deletion of E2f1-3 in the small intestine of mice suppressed the ectopic expression of E2F targets and cell proliferation caused by Rb-deficiency. Surprisingly, E2f1-3 deletion failed to arrest the proliferation of intestinal cells containing an intact Rb gene, and instead led to E2F target derepression and apoptosis. Experiment Overall Design: Total RNA of crypts and villi from wild-type, Rb-/-, E2f1-/-, E2f2-/-, E2f3-/-, E2f1-/-, E2f2-/-, and E2f3-/- small intestines. Small intestines were harvested 7 days after mice were injected intraperitoneally with beta-napthoflavone.
2010-01-19 | E-GEOD-16454 | biostudies-arrayexpress
Project description:Advances in genomic signatures have begun to dissect breast cancer heterogeneity, and application of these signatures will allow the prediction of which pathways are important in tumor development. Here we used genomic signatures to predict involvement of specific E2F transcription factors in Myc-induced tumors. We genetically tested this prediction by interbreeding Myc transgenics with mice lacking various activator E2F alleles. Tumor latency decreased in the E2F1 mutant background and significantly increased in both the E2F2 and E2F3 mutants. Investigating the mechanism behind these changes revealed a reduction in apoptosis in the E2F1 knockout strain. E2F2 and E2F3 mutant backgrounds alleviated Myc effects on the mammary gland, reducing the susceptible tumor target population. Gene expression data from tumors revealed that the E2F2 knockout background resulted in fewer tumors with EMT, corresponding with a reduction in probability of Ras activation. In human breast cancer we found that a low probability of E2F2 pathway activation was associated with increased relapse-free survival time. Together these data illustrate the predictive utility of genomic signatures in deciphering the heterogeneity within breast cancer and illustrate the unique genetic requirements for individual E2Fs in mediating tumorigenesis in both mouse models and human breast cancer. MMTV-Myc tumors were generated in an E2F wild-type, E2F1 null, E2F2 null and E2F3 heterozygous background. When the primary tumor reached the endpoint, the tumors were flash frozen. 20 tumors from each genotype were selected for microarray analysis.
2011-12-29 | E-GEOD-24594 | biostudies-arrayexpress
Project description:Rb and E2F are thought to play antagonistic roles in celll proliferation. However, this model is based mostly from in vitro cell culture systems. We used small intestines to test this model in vivo. We found that deletion of E2f1-3 in the small intestine of mice suppressed the ectopic expression of E2F targets and cell proliferation caused by Rb-deficiency. Surprisingly, E2f1-3 deletion failed to arrest the proliferation of intestinal cells containing an intact Rb gene, and instead led to E2F target derepression and apoptosis.
2009-12-17 | GSE16454 | GEO
Project description:The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC enhancer binding directly promotes cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNAPII, rather than regulating RNAPII pause-release as is the case at promoters. This is mediated by MYC-induced H3K9 demethylation by KDM3A and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. Thus, we propose that MYC drives prognostic cancer type-specific gene programs by promoting RNAPII recruitment to enhancers through induction of an epigenetic switch.
2023-11-30 | PXD039586 | Pride
Project description:Advances in genomic signatures have begun to dissect breast cancer heterogeneity, and application of these signatures will allow the prediction of which pathways are important in tumor development. Here we used genomic signatures to predict involvement of specific E2F transcription factors in Myc-induced tumors. We genetically tested this prediction by interbreeding Myc transgenics with mice lacking various activator E2F alleles. Tumor latency decreased in the E2F1 mutant background and significantly increased in both the E2F2 and E2F3 mutants. Investigating the mechanism behind these changes revealed a reduction in apoptosis in the E2F1 knockout strain. E2F2 and E2F3 mutant backgrounds alleviated Myc effects on the mammary gland, reducing the susceptible tumor target population. Gene expression data from tumors revealed that the E2F2 knockout background resulted in fewer tumors with EMT, corresponding with a reduction in probability of Ras activation. In human breast cancer we found that a low probability of E2F2 pathway activation was associated with increased relapse-free survival time. Together these data illustrate the predictive utility of genomic signatures in deciphering the heterogeneity within breast cancer and illustrate the unique genetic requirements for individual E2Fs in mediating tumorigenesis in both mouse models and human breast cancer.
2011-12-29 | GSE24594 | GEO
Project description:Fbw7 is a tumor suppressor protein that regulates the degradation of a multitude of oncogenic substrates, such as c-Jun, c-Myc, Notch1 intracellular domain, and cyclin E. Loss of FBXW7 expression is relatively common in breast cancer. Despite this, the effect of FBXW7 loss on breast tumorigenesis has not been examined. We demonstrate here that loss of FBXW7 is sufficient for breast tumorigenesis. Many of Fbw7’s substrates are transcription factors or are closely linked to transcription factor pathways. As loss of Fbw7 results in upregulation of multiple substrates, we set out to determine which, if any of these transcription factor pathways predominate early after Fbw7 loss and after tumorigenesis. To address this, we employed genome-wide RNA sequencing to examine transcription factor pathway alterations early after FBXW7 loss in non-tumor breast epithelial cells as well as after prolonged FBXW7 loss, in tumor samples. We demonstrate an early upregulation of E2F and c-Myc pathways that is reinforced upon tumorigenesis. These findings suggest E2F and c-Myc as important targetable pathways in Fbw7 low breast cancer patients.
2020-07-15 | GSE144690 | GEO
Project description:Most E2F-binding sites repress transcription through the recruitment of Retinoblasoma (RB) family members until the end of the G1 cell-cycle phase. Although the MYB promoter contains an E2F-binding site, its transcription is activated shortly after the exit from quiescence, before RB family members inactivation, by unknown mechanisms. We had previously uncovered a nuclear factor distinct from E2F, Myb-sp, whose DNA-binding site overlapped the E2F element and had hypothesized that this factor might overcome the transcriptional repression of MYB by E2F-RB family members. We have purified Myb-sp and discovered that Myc-associated zinc finger proteins (MAZ) are major components. We show that various MAZ isoforms are present in Myb-sp and activate transcription via the MYB-E2F element. Moreover, while forced RB or p130 expression repressed the activity of a luciferase reporter driven by the MYB-E2F element, co-expression of MAZ proteins not only reverted repression, but also activated transcription. Finally, we show that MAZ binds the MYB promoter in vivo, that its binding site is critical for MYB transactivation, and that MAZ knockdown inhibits MYB expression during the exit from quiescence. Together, these data indicate that MAZ is essential to bypass MYB promoter repression by RB family members and to induce MYB expression.
2017-10-04 | PXD006857 | Pride