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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Simon Andrews

PROVIDER: E-GEOD-82149 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

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

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-08-04 | E-GEOD-82150 | biostudies-arrayexpress

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

2016-08-04 | GSE82149 | GEO

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

2016-08-04 | GSE82148 | GEO

ChIP-seq data of Epstein-Barr Virus Nuclear Antigen Leader ProteinM-BM- (EBNALP)

Project description:Epstein-Barr-Virus (EBV) Nuclear Antigens EBNALP and EBNA2 are co-expressed in EBV infected B-lymphocytes and are critical for Lymphoblastoid Cell Line (LCL) growth. EBNALP removes NCOR1 and RBPJ repressive complexes from promoter and enhancer sites and EBNA2 mostly activates transcription from distal enhancers. ChIP-seqs found EBNALP at 19,224 LCL sites, which were 33% promoter associated. EBNALP was associated with 10 transcription factor (TF) clusters that included YY1(63%), SP1(62%), PAX5(59%), BATF(50%), IRF4(49%), RBPJ(43%), ETS1(39%), PU.1(37%), RAD21(33%), NF-kB(31%), TBLR1(26%), ZNF143(24%), CTCF(23%), SMC3(21%), and EBF(17%). EBNALP sites had higher H3K4me3, H3K9ac, H3K27ac, H2Az, and RNA Pol II signals than EBNA2 sites and had similar transcription effects. EBNALP co-localized with 29% of 19,845 EBNA2 sites. EBNALP/EBNA2 sites were similar to EBNALP sites in promoter localization, associated cell TFs, Pol II, H3K4me3, H3K9ac, H3K27ac, and H2Az signals. EBNALP and EBNA2 promoter sites were more transcriptionally active than EBNALP or EBNA2 promoter sites. EBNALP was at the enhancer or promoter of myc and MYC affected genes, including cyclin D2, and bcl2. EBNALP at promoters with DNA looping and transcription factors, is positioned to deplete repressors from enhancers and promoters, enable chromatin remodeling, and transcription activation. Two EBNALP ChIP-seq replicates from IB4 LCL are analyzed in this study.

2013-07-31 | E-GEOD-49338 | biostudies-arrayexpress

ChIP-seq data of Epstein-Barr Virus Nuclear Antigen Leader Protein (EBNALP)

2013-07-31 | GSE49338 | GEO

Epstein-Barr Virus Exploits Intrinsic B-Lymphocyte Transcription Programs to Achieve Immortal Cell Growth

Project description:Epstein-Barr Virus Nuclear Antigen 2 (EBNA2) gene regulation through the cell RBPJ transcription factor (TF) is essential for conversion of resting B-lymphocytes (RBLs) into Lymphoblastoid Cell Lines (LCLs). ChIP-seq investigation of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5151 and RBPJ at 10,529 sites. EBNA2 was 72% localized with RBPJ, predominantly at intergenic and intronic sites and only 14% at promoter sites. EBNA2/RBPJ sites were enriched for Early B-cell Factor (EBF, 60%), RUNX(41%), ETS(35%), NF-ï«B(31%), and PU.1(17%) TF motifs. Using ENCyclopedia Of DNA Elements (ENCODE) LCL data, EBF, RELA, and PU.1 were found at 54%, 31%, and 17% of EBNA2 sites. K-Means clustering of EBNA2 site associated TFs found RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX ranked highest to lowest in nearly symmetric H3K4me1 signal distribution and nucleosome depletion, marks of active chromatin. Although quantitatively less, high level nearly symmetric H3K4me1 signals with nucleosome depletion at the same sites in RBLs was remarkably similar to LCLs, indicating that EBNA2 localizes into a pre-established RBL chromatin pattern, which likely evolved to enable RBL antigen-induced proliferation. EBF was critical for EBNA2 activation of the EBV LMP1 promoter. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 up-regulated genes. Fluorescence In Situ Hybridization (FISH), conditional EBNA2 FISH, Chromatin Conformation Capture (3C), and 3C q-PCR, linked EBNA2/RBPJ enhancers 428 kb 5' of MYC to MYC. These data support the hypothesis that EBNA2 evolved to exploit the RBL transcription framework to drive B-lymphocyte proliferation in primary human infection. EBNA2 and RBPJ ChIP-seq from IB4 LCL

2011-07-01 | E-GEOD-29498 | biostudies-arrayexpress

Epstein-Barr Virus Exploits Intrinsic B-Lymphocyte Transcription Programs to Achieve Immortal Cell Growth

2011-07-01 | GSE29498 | GEO

RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth

Project description:In B cells infected by the cancer-associated Epstein-Barr virus (EBV), RUNX3 and RUNX1 transcription is manipulated to control cell growth. The EBV-encoded EBNA2 transcription factor (TF) activates RUNX3 transcription leading to RUNX3-mediated repression of the RUNX1 promoter and the relief of RUNX1-directed growth repression. We show that EBNA2 activates RUNX3 through a specific element within a -97 kb super-enhancer in a manner dependent on the expression of the Notch DNA-binding partner RBP-J. We also reveal that the EBV TFs EBNA3B and EBNA3C contribute to RUNX3 activation in EBV-infected cells by targeting the same element. Uncovering a counter-regulatory feed-forward step, we demonstrate EBNA2 activation of a RUNX1 super-enhancer (-139 to -250 kb) that results in low-level RUNX1 expression in cells refractory to RUNX1-mediated growth inhibition. EBNA2 activation of the RUNX1 super-enhancer is also dependent on RBP-J. Consistent with the context-dependent roles of EBNA3B and EBNA3C as activators or repressors, we find that these proteins negatively regulate the RUNX1 super-enhancer, curbing EBNA2 activation. Taken together our results reveal cell-type specific exploitation of RUNX gene super-enhancers by multiple EBV TFs via the Notch pathway to fine tune RUNX3 and RUNX1 expression and manipulate B-cell growth.

2016-03-03 | GSE76869 | GEO

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

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