Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Suppression of oncogenic super enhancers in MYC-dependent AMLs by NR4A Nuclear Receptors

ABSTRACT: NR4A nuclear receptors are tumor suppressors of acute myeloid leukemia (AML) that are silenced in AML at the level of transcription elongation. Using RNA-Seq, we show that NR4As inhibit leukemic cell growth largely through suppression of MYC pathway genes. MYC is highly expressed in AML and contributes to AML progression and therapeutic resistance. MYC expression in AML is driven by a super enhancer cluster 1.8Mbp downstream of the MYC locus, which is highly sensitive to therapeutic intervention, including treatment with BET inhibitors. We recently identified dihydroergotamine (DHE) as an FDA-approved drug that strongly induces NR4A transcription in AML cells and operates effectively as an antileukemic therapy. RNA-Seq in MOLM-14 identified MYC as the most statistically repressed target of DHE. Using ChIP-Seq for MED1 as a readout for Mediator occupancy, we identified super enhancers in MOLM-14 cells and show that treatment with DHE significantly suppresses MED1 signal across a subset of super enhancers, including the MYC super enhancer. Finally, we demonstrate that NR4As are broadly associated with global super enhancers, including sites where super enhancer activity is retained, reduced, or gained.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124963 | GEO | 2020/01/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Genome wide mapping of NR4A binding reveals cooperativity with ETS factors to promote epigenetic activation of distal enhancers in acute myeloid leukemia cells [array]

Project description:NR4As are critical tumor suppressors of acute myeloid leukemia (AML) whose expression is broadly silenced in leukemia initiating cell enriched populations from human patients relative to normal hematopoietic stem/progenitor cells. Rescued NR4A expression in human AML cells inhibits proliferation and reprograms AML gene signatures via transcriptional mechanisms that remain to be elucidated. By intersecting an acutely regulated, NR4A1 dependent transcriptional profile with genome wide NR4A binding distribution, we now identify an NR4A targetome of 685 genes that are directly regulated by NR4A1. We show that NR4As regulate gene transcription primarily through interaction with distal enhancers that are co-enriched for both NR4A1 and ETS transcription factor motifs. Using a subset of NR4A activated genes, we demonstrate that the ETS factors ERG and FLI-1 are required for activation of NR4A bound enhancers and NR4A target gene induction. NR4A1 dependent recruitment of ERG and FLI-1 promotes binding of p300 histone acetyl transferase to activate NR4A bound enhancers. These findings disclose novel epigenetic mechanisms by which NR4As and ETS factors cooperate to drive NR4A dependent gene transcription in human AML cells. Transcriptome analysis in triplicate 6hr after exogenous NR4A1 expression compared to GFP transfection control.

2016-03-22 | E-GEOD-79490 | biostudies-arrayexpress

Genome wide mapping of NR4A binding reveals cooperativity with ETS factors to promote epigenetic activation of distal enhancers in acute myeloid leukemia cells [ChIP-Seq]

2016-03-22 | E-GEOD-79491 | biostudies-arrayexpress

Genome wide mapping of NR4A binding reveals cooperativity with ETS factors to promote epigenetic activation of distal enhancers in acute myeloid leukemia cells [ChIP-Seq]

2016-03-22 | GSE79491 | GEO

Genome wide mapping of NR4A binding reveals cooperativity with ETS factors to promote epigenetic activation of distal enhancers in acute myeloid leukemia cells [array]

2016-03-22 | GSE79490 | GEO

Suppression of oncogenic super enhancers in MYC-dependent AMLs by NR4A Nuclear Receptors

Project description:Suppression of oncogenic super enhancers in MYC-dependent AMLs by NR4A Nuclear Receptors

| PRJNA514709 | ENA

Hierarchy within the mammary STAT5-driven Wap super-enhancer

Project description:Super-enhancers comprise of dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate their role in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-Seq for the master regulator STAT5, the glucocorticoid receptor, H3K27ac and MED1, identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5 binding sites within its three constituent enhancers. Individually, only the most distal site displayed significant enhancer activity. However, combinatorial mutations showed that the 1,000-fold gene induction relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer, suggesting an enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insight into the complexity of cell-specific and hormone-regulated genes. ChIP-Seq for STAT5A, GR, H3K27ac, MED1, NFIB, ELF5, RNA Pol II, and H3K4me3 in wild type (WT) mammary tissues at day one of lactation (L1), and ChIP-Seq for STAT5A, GR, H3K27ac, MED1, NFIB, ELF5, and H3K4me3 in WT mammary tissues at day 13 of pregnancy (p13). ChIP-Seq for STAT5A, GR, H3K27a in Wap-delE1a, -delE1b, -delE1c, -delE2 and -delE3 mutant mammary tissues at L1, and ChIP-Seq for NFIB and ELF5 in Wap-delE1b and -delE1c mutant mammary tissues at L1. ChIP-Seq for H3K4me3 in mammary-epthelial cells at p13 and L1. DNase-seq in WT mammary tissues at L1 and DNase-seq in Wap-delE1a, -delE1c, and -delE3 mutant mammary tissues at L1.

2016-05-31 | E-GEOD-74826 | biostudies-arrayexpress

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes

Project description:The master transcription factors Oct4, Sox2 and Nanog bind enhancer elements and recruit the Mediator co-activator to activate much of the gene expression program of embryonic stem cells (ESCs). We report here that these ESC master transcription factors and Mediator form M-bM-^@M-^\super-enhancersM-bM-^@M-^] at most genes that are known to control the pluripotent state, including those encoding the master transcription factors themselves. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of Oct4 and Mediator. Super-enhancers stimulate considerably higher transcription than typical enhancers in reporter vectors. ESC differentiation causes preferential loss of expression of super-enhancer -associated genes. Super-enhancers are also found at key cell identity genes in differentiated cells. These results implicate super-enhancers in the control of mammalian cell identity and differentiation and suggest that these elements might generally be used to identify genes that control cell-type specific gene expression programs in many mammalian cells. ChIP-Seq and RNA-seq of Med1 in ZHBTc4 ES during treatment with doxycycline. ChIP-Seq data of Med1 in 38B9 pro-B cells.

2013-01-02 | E-GEOD-42474 | biostudies-arrayexpress

CTCF-dependent enhancer hijacking by the EVI1 oncogene in leukemia

Project description:Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements which are often therapy resistant. In a cohort of primary t(3;8)(q26;q24) AML samples we observed the translocation of a MYC super-enhancer to EVI1. We generated a patient-based t(3;8)(q26;q24) model in vitro using CRISPR-Cas9 technology and demonstrated hyper-activation of EVI1 by the hijacked MYC super-enhancer. One MYC super-enhancer element in particular, which recruits early hematopoietic regulators, is critical for EVI1 expression and enhancer-promoter interaction. This interaction is facilitated by a CTCF-bound motif upstream of the EVI1 promoter that acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of 3q26-rearranged AML samples point to a common mechanism by which EVI1 uses this CTCF-bound enhancer-docking site to hijack early hematopoietic enhancers.

| EGAS00001004808 | EGA

Epstein-Barr Virus oncoprotein super-enhancers control B cell growth

Project description:Super-enhancers are principal determinants of cell transcription, development, phenotype, and oncogenesis, not yet implicated in host-pathogen interactions. We found four Epstein-Barr virus (EBV) oncoproteins and five EBV-activated NF-M-oM-^AM-+B subunits co-occupying thousand of enhancer sites in EBV-transformed lymphoblastoid cells (LCLs). Of these, 187 had markedly higher and broader histone H3K27ac signals characteristic of super-enhancer formation, and were designated M-bM-^@M-^\EBV super-enhancersM-bM-^@M-^]. EBV super-enhancer associated genes included MYC and BCL2, which enable LCL proliferation and survival. EBV super-enhancers were enriched for specific B cell transcription factor motifs and had high STAT5 and NFAT co-occupancy. EBV super-enhancer associated genes were more highly expressed than other LCL genes. Disruption of EBV super-enhancers by the bromo-domain inhibitor, JQ1, by conditional inactivation of an EBV oncoprotein or NF-M-oM-^AM-+B, decreased MYC or BCL2 gene expression and arrested LCL growth. These findings provide novel insights into the mechanisms by which EBV causes lymphoproliferation and identify opportunities for therapeutic intervention. ChIP-seq was used to define the BRD4 genome-wide landscape in GM12878 lymphoblastoid cells.

2014-11-01 | E-GEOD-62912 | biostudies-arrayexpress

DNA accessibility sites requiring SWI/SNF activity in AML [ATAC-seq]

Project description:To reveal the genome-wide targets of SWI/SNF complexes in AML cells, we performed ATAC-seq in THP-1, MOLM-13, and MV-4-11 cells with or without the SWI/SNF ATPase BRM014. Analysis of the locations decreased following 24 or 72 h after addition of BRM014 revealed that SWI/SNF-dependent sites are located at enhancers occupied by PU.1, especially the blood enhancer cluster (BENC), a set of enhancers that drives expression of MYC.

2023-01-10 | GSE190721 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data