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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79490 | GEO | 2016/03/22

SECONDARY ACCESSION(S): PRJNA315978

REPOSITORIES: GEO

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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]

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. NR4A1 ChIP-seq after exogenous NR4A1 expression

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 [array]

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 | GSE79491 | GEO

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

Project description: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.

2020-01-11 | GSE124963 | GEO

Expression data of mouse hematopoietic cells, Nr4a1/3 wild type and double mutant

Project description:We investigate the cellular and molecular mechanisms of tumor suppression by NR4A1 and NR4A3, and show a cell intrinsic essential function in maintenance of hematopoietic stem cell (HSC) homeostasis. In the absence of Nr4a1/3, HSC lost quiescence, became highly proliferative leukemia-stem cell (LSC) that transplanted AML to recipient mice. We further revealed that loss of NR4A1/3 leads to deregulated expression of the key cell cycle regulator Cdkn1c (P57), c-Myc oncogene, and glucose metabolic genes leading to enhanced aerobic glycolysis or Warburg effect in LSCs. Reintroduction of Nr4a1 in LSCs restored HSC quiescence, and reversed Nr4a1/3 deficiency induced P57 suppression and c-Myc overexpression. Collectively, we identify an essential role of Nr4a1/3 in coordinately regulating cell cycle entry and glucose metabolism to prevent uncontrolled stem cell proliferation and AML transformation. These results have major implications for designing therapeutic strategies in AML. To identify NR4A-dependent molecular signaling pathways that may control HSC homeostasis, we performed genome-wide transcript profiling of Lin-Sca1+ (LS) cells from WT and DKO mice. For Affymetrix analysis, we generated three independent pools of RNA from sorted LS cells from 10-20 WT or DKO (2- to 3-week-old) mice per sample.

2013-12-30 | E-GEOD-31042 | biostudies-arrayexpress

Genome-wide ChIP-seq analysis of Nr4a1 binding sites in regulatory T (Treg) cells

Project description:We have revealed that Nr4a family nuclear orphan receptors broadly regulate a transcriptional program in Treg cells. In this study, to give an insight into Nr4a-mediated regulation of the transcriptional program in Treg cells, we performed ChIP-seq experiment using anti-Nr4a1 antibodies and a chromatin lysate from Treg cells. Examination of Nr4a1 binding sites in mouse Treg cells.

2015-06-30 | E-GEOD-70417 | biostudies-arrayexpress

Nuclear receptor subfamily 4A signaling as a key disease pathway of CD1c+ dendritic cell dysregulation in systemic sclerosis [RNA-seq]

Project description:Objectives: To identify key pathways, transcriptional regulators and epigenetic mechanisms underlying conventional dendritic cell (cDC) alteration in Systemic Sclerosis (SSc). Methods: Transcriptomic profiling was performed on CD1c+ cDCs isolated from peripheral blood samples obtained from 12 healthy donors and 48 SSc patients with all major disease subtypes. Differential expression analysis comparing the different SSc subtypes and healthy donors was performed to uncover genes dysregulated in SSc. To identify biologically relevant pathways, a gene co-expression network was built using the Weighted Gene Correlation Network Analysis. We validated the role of key transcriptional regulators using ChIP-sequencing and in vitro functional assays. Results: We identified 17 modules of co-expressed genes in cDCs that correlated with SSc subtypes and key clinical traits. A module of immune regulatory genes was markedly down regulated in patients with the diffuse SSc subtype suffering from severe fibrosis. Gene regulatory network analysis performed on the immune regulatory module predicted NR4A (nuclear receptor 4A) subfamily (NR4A1, NR4A2, NR4A3) genes as the master transcriptional mediators of inflammation. Indeed, ChIP-sequencing analysis of cDCs supported that these NR4A members target numerous differentially expressed genes in SSc cDCs. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDCs and modulates T-cells activation. Conclusions: NR4A1, NR4A2 and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDCs. Thus, the NR4A family represent novel potential targets to restore cDC homeostasis in SSc.

2023-03-22 | GSE186198 | GEO

Nuclear receptor subfamily 4A signaling as a key disease pathway of CD1c+ dendritic cell dysregulation in systemic sclerosis [ChIP-seq]

2023-03-22 | GSE186197 | GEO

Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis. [RNA-seq]

Project description:Chromosomal rearrangements resulting in the fusion of TMRPSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.

2018-08-02 | GSE110656 | GEO

Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis.[ChIP-seq]

2018-08-02 | GSE110655 | GEO

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