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MYC enhancer invasion promotes prognostic cancer type-specific gene programs through an epigenetic switch [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224611 | GEO | 2023/11/29

REPOSITORIES: GEO

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MYC enhancer invasion promotes prognostic cancer type-specific gene programs through an epigenetic switch

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

MYC enhancer invasion promotes prognostic cancer type-specific gene programs through an epigenetic switch [CAGE-seq]

2023-11-29 | GSE224612 | GEO

MYC enhancer invasion promotes prognostic cancer type-specific gene programs through an epigenetic switch [ATAC-seq]

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MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch

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 directly regulates enhancer activity to promote cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNA polymerase II (RNAPII), rather than regulating RNAPII pause-release, as is the case at promoters. This process is mediated by MYC-induced H3K9 demethylation and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. We propose that MYC drives prognostic cancer type-specific gene programs through induction of an enhancer-specific epigenetic switch, which can be targeted by BET and GCN5 inhibitors.

2023-11-29 | GSE224609 | GEO

Control of cell identity and early neural fate commitment by the enhancer module of Integrator

Project description:Lineage-specific transcription factors (TFs) operate as master orchestrators of developmental processes by activating select cis-regulatory enhancers and proximal promoters. Direct DNA binding of TFs ultimately drives context-specific recruitment of the basal transcriptional machinery that comprises RNA Polymerase II (RNAPII) and a host of polymerase-associated multiprotein complexes, including the metazoan-specific Integrator complex. Integrator is primarily known to modulate RNAPII processivity and to surveil RNA integrity across coding genes. Here we show an enhancer module of Integrator that directs cell fate specification by promoting epigenetic changes and TF binding at neural enhancers. Depletion of Integrator’s INTS10 upends neural traits and derails cells towards mesenchymal identity. Commissioning of neural enhancers relies on Integrator’s enhancer module, which stabilizes SOX2 binding at chromatin upon exit from pluripotency. We propose Integrator as a functional bridge between enhancers and promoters and a main driver of early development, providing new insight into a growing family of neurodevelopmental syndromes.

2024-08-15 | PXD054928 | Pride

MYC activation and BCL2L11 silencing by a tumor virus through the large-scale reconfiguration of enhancer-promoter hubs [EREB]

Project description:Lymphomagenesis in the presence of deregulated MYC expression requires suppression of MYC-driven apoptosis, often through downregulation of the pro-apoptotic BCL2L11 gene (Bim). Transcription factors (EBNAs) encoded by the lymphoma-associated Epstein-Barr virus (EBV) activate MYC and silence BCL2L11. We show that EBNA2 upregulates MYC by reconfiguring the 3 Mb MYC locus to increase upstream and decrease downstream enhancer-promoter interactions. EBNA2 recruits the SWI/SNF ATPase BRG1 to drive MYC enhancer-promoter interactions. MYC-Immunoglobulin translocation breakpoints in EBV-positive endemic Burkitt lymphoma localise to EBNA2-activated upstream MYC regions. This implicates EBV in the genesis and localisation of breakpoints, since active enhancers are targeted by activation-induced cytidine deaminase. We identify a novel haematopoietic BCL2L11 enhancer hub that is inactivated by EBNA3A and EBNA3C through recruitment of the H3K27 methyltransferase EZH2. Reversal of enhancer inactivation using an EZH2 inhibitor upregulates BCL2L11 and induces apoptosis. EBV therefore drives lymphomagenesis by hijacking long-range enhancer hubs and specific cellular co-factors. A study of MYC enhancer-promoter interactions using 4C on induction of MYC by the Epstein-Barr virus transcription factor EBNA2 in a lymphoblastoid cell line.

2016-08-04 | E-GEOD-82149 | biostudies-arrayexpress

Altered topology drives oncogenic programs in SDH-deficient GIST

Project description:<p>Metabolic lesions with pleiotropic effects on epigenetic regulation and other cellular processes are widely implicated in cancer, yet their oncogenic mechanisms remain poorly understood. Succinate dehydrogenase (SDH) deficiency causes a subset of gastrointestinal stromal tumors (GISTs) with DNA hyper-methylation. Here we associate this hyper-methylation with changes in chromosome topology that activate oncogenic programs. To investigate epigenetic alterations in this disease, we systematically mapped DNA methylation, CTCF insulators, enhancers and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes share similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on disrupted insulators that partitions super-enhancers from FGF3, FGF4 and the KIT oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancers and oncogenes. CRISPR-mediated excision of the corresponding CTCF motif in an SDH-intact model disrupted the boundary and up-regulated FGFs and KIT expression. Our findings reveal how a metabolic lesion destabilizes chromatin structure to facilitate the initiation and selection of epigenetic alterations that drive oncogenic programs in the absence of canonical mutations.</p>

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MYC activation and BCL2L11 silencing by a tumor virus through the large-scale reconfiguration of enhancer-promoter hubs [Bcell]

Project description:Lymphomagenesis in the presence of deregulated MYC expression requires suppression of MYC-driven apoptosis, often through downregulation of the pro-apoptotic BCL2L11 gene (Bim). Transcription factors (EBNAs) encoded by the lymphoma-associated Epstein-Barr virus (EBV) activate MYC and silence BCL2L11. We show that EBNA2 upregulates MYC by reconfiguring the 3 Mb MYC locus to increase upstream and decrease downstream enhancer-promoter interactions. EBNA2 recruits the SWI/SNF ATPase BRG1 to drive MYC enhancer-promoter interactions. MYC-Immunoglobulin translocation breakpoints in EBV-positive endemic Burkitt lymphoma localise to EBNA2-activated upstream MYC regions. This implicates EBV in the genesis and localisation of breakpoints, since active enhancers are targeted by activation-induced cytidine deaminase. We identify a novel haematopoietic BCL2L11 enhancer hub that is inactivated by EBNA3A and EBNA3C through recruitment of the H3K27 methyltransferase EZH2. Reversal of enhancer inactivation using an EZH2 inhibitor upregulates BCL2L11 and induces apoptosis. EBV therefore drives lymphomagenesis by hijacking long-range enhancer hubs and specific cellular co-factors. A study of MYC enhancer-promoter interactions using 4C on induction of MYC by Epstein-Barr virus infection of CD19+ primary B cells. B cells physiologically activated by treatment with CD40 ligand and IL-4 were studied as a control.

2016-08-04 | E-GEOD-82148 | biostudies-arrayexpress

Genome wide analysis of FOXO3 transcription regulation through RNA pol II profiling

Project description:FOXO transcription factors are key players in diverse cellular processes affecting tumorigenesis, stem cell maintenance and lifespan. To gain insight into mechanisms of FOXO regulated target gene expression, we studied genome-wide effects of FOXO3 activation. Profiling RNA polymerase II changes shows FOXO3 regulates gene expression through transcription initiation. Correlative analysis of FOXO3 and RNA polymerase II ChIP-seq profiles demonstrates FOXO3 to act as a transcriptional activator. Furthermore, this analysis reveals a significant part of FOXO3 gene regulation proceeds through enhancer regions. FOXO3 binds to pre-existing enhancers and further activates these enhancers as shown by changes in histone acetylation and RNA polymerase II recruitment. In addition, FOXO3-mediated enhancer activation correlates with regulation of adjacent genes and pre-existence of chromatin loops between FOXO3 bound enhancers and target genes. Combined, our data elucidate how FOXOs regulate gene transcription and provide insight into mechanisms by which FOXOs can induce different gene expression programs depending on chromatin architecture. Paper with published gene expression: PMID 22139133. Examination of FOXO3 binding and changes in RNAPII occupancy (0, 4, 24 hours after induction) in colorectal cell line

2012-11-15 | E-GEOD-35486 | biostudies-arrayexpress

Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia

Project description:Despite absent expression in normal hematopoiesis, the Forkhead factor FOXC1, a critical mesenchymal differentiation regulator, is highly expressed in ~30% of HOXAhigh AML to confer blocked monocyte/macrophage differentiation. Through integrated proteomics and bioinformatics, we discovered that FOXC1 and RUNX1 interact through Forkhead and Runt domains respectively and cooccupy primed and active enhancers distributed close to differentiation genes. FOXC1 stabilises association of RUNX1, HDAC1 and Groucho repressor TLE3 to limit enhancer activity: FOXC1 knockdown induced loss of repressor proteins, gain of CEBPA binding, enhancer acetylation and upregulation of nearby genes, including KLF2. Furthermore, it triggered genome-wide redistribution of RUNX1, TLE3 and HDAC1 from enhancers to promoters leading to repression of self-renewal genes including MYC and MYB. Our studies highlight RUNX1 and CEBPA transcription factor swapping as a feature of leukemia cell differentiation, and reveal that FOXC1 prevents this by stabilising enhancer binding of a RUNX1/HDAC1/TLE3 transcription repressor complex, to oncogenic effect.

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