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IRF2BP2 counteracts the ATF7/JDP2 heterodimer to prevent inflammatory overactivation in AML cells [RNA-seq]

ABSTRACT: Acute myeloid leukemia (AML) is a hematological malignancy characterized by abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of cell-intrinsic inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2, which is involved in activating inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene-activating function. Loss of IRF2BP2 leads to overactivation of inflammatory pathways, resulting in strongly reduced proliferation. Our research indicates that a precise equilibrium between activating and repressive transcriptional mechanisms creates a pro-oncogenic inflammatory environment in AML cells. The ATF7/JDP2-IRF2BP2 regulatory axis is likely a key regulator of this process and may, therefore, represent a promising therapeutic vulnerability for AML. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229593 | GEO | 2024/05/07

REPOSITORIES: GEO

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IRF2BP2 counteracts the ATF7/JDP2 heterodimer to prevent inflammatory overactivation in AML cells

Project description:Acute myeloid leukemia (AML) is a hematological malignancy characterized by the abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator that has been implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that in AML cells IRF2BP2 interacts with the transcriptional heterodimer ATF7/JDP2, which is involved to activate inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene activating function. Loss of IRF2BP2 leads to the overactivation of inflammatory pathways, resulting in immediate cell death. Our findings suggest that a delicate balance of activating and repressive transcriptional mechanisms establishes a pro-oncogenic inflammatory set-up in AML cells, and that manipulation of the ATF7/JDP2-IRF2BP2 regulatory axis may offer a potential vulnerability for AML treatment. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment.

2024-05-16 | PXD041817 | Pride

IRF2BP2 counteracts the ATF7/JDP2 heterodimer to prevent inflammatory overactivation in AML cells [ChIP-seq]

Project description:Acute myeloid leukemia (AML) is a hematological malignancy characterized by abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of cell-intrinsic inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2, which is involved in activating inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene-activating function. Loss of IRF2BP2 leads to overactivation of inflammatory pathways, resulting in strongly reduced proliferation. Our research indicates that a precise equilibrium between activating and repressive transcriptional mechanisms creates a pro-oncogenic inflammatory environment in AML cells. The ATF7/JDP2-IRF2BP2 regulatory axis is likely a key regulator of this process and may, therefore, represent a promising therapeutic vulnerability for AML. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment.

2024-05-07 | GSE229594 | GEO

ATF2 and ATF7 mediation of intestinal repair in murine colitis model

Project description:AP1 transcription factor family members: activating transcription factor 2 (ATF2) and activating transcription factor 7 (ATF7) have highly redundant functions due to homology and hence overlapping DNA-binding sites. The role of these transcription factors in intestinal epithelial homeostasis and repair has not been critically examined. Here, by using an intestine-specific deletion of ATF2 combined with body wide deletion of ATF7 in mice we assess the role of these proteins during intestinal homeostasis and repair after inflammation.

2019-12-17 | GSE142065 | GEO

IRF2BP2 counteracts the ATF7/JDP2 heterodimer to prevent inflammatory overactivation in AML cells.

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-07 | GSE229595 | GEO

Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [RNA-seq]

Project description:Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance of their leukemic state and can be exploited as a cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens to discover genetic vulnerabilities in acute myeloid leukemia (AML) cells that are also implicated in inflammatory pathways. We identified the immune modulator interferon regulatory factor 2 binding protein 2 (IRF2BP2) as a selective dependency in AML. We validated AML cell dependency on IRF2BP2 with genetic and protein degradation approaches in vitro and genetically in vivo. Chromatin and global gene expression studies demonstrated that IRF2BP2 represses IL1B/TNFA signaling via NF-KB, and IRF2BP2 perturbation results in an acute inflammatory state leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for regulated cell death, and establish IRF2BP2-mediated transcriptional repression as a mechanism for blast survival.

2022-05-23 | GSE168648 | GEO

Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [ChIP-seq]

2022-05-23 | GSE168647 | GEO

The Transcription Factor ATF7 Controls Adipocyte Differentiation and Thermogenic Gene Programming

Project description:The adipocytes functions as a central organ in the regulation of metabolic homeostasis. Factors which contribute to the adipocyte differentiation and function would be the promising targets to combat the obesity and associated metabolic disorders. The activating transcription factor 7 (ATF7), a stress-responsive chromatin regulator, has recently been shown to be involved in the energy metabolism; however, the underlying mechanisms are still unknown. Here, we show that ATF7 is required for adipocyte differentiation and it interacts with histone dimethyltransferase G9a in adipocyte to repress the interferon-stimulated genes (ISGs) expression, which suppresses adipogenesis. Ablation of ATF7 promotes the beige biogenesis and browning of inguinal white adipose tissue (iWAT). ATF7 binds to the transcription regulatory regions of Ucp1 gene, and silences it by maintaining the histone H3K9 dimethylation level. These results establish the multifunction of ATF7 in adipocyte and provide molecular insights into the epigenetic control of development and function of adipose tissues. We used microarrays to identify the differentatial expression genes in the inguinal white adipose tissue of ATF7 KO mice.

2018-11-10 | GSE122374 | GEO

The Transcription Factor ATF7 Controls Adipocyte Differentiation and Thermogenic Gene Programming.

2018-11-09 | GSE122346 | GEO

IRF2BP2 Modulates the Crosstalk between Glucocorticoid and TNF Signaling

Project description:Here we have analyzed the role of interferon regulatory factor-2 binding protein-2 (IRF2BP2) in glucocorticoid and tumor necrosis factor alpha (TNF) signaling. We used ChIP-seq to analyze chromatin binding of IRF2BP2 in glucocorticoid (dexamethasone, dex) and vehicle treated HEK293 cells expressing GR (HEK293-GR). Furthermore, we used RNA-seq to analyze how silencing of IRF2BP2 modulates transcriptional responses to dex treatment in HEK293-GR cells, and dex, TNF and co-treatment (dex and TNF, DT) in A549 cells.

2019-06-03 | GSE124636 | GEO

ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory (ChIP)

Project description:Immunological memory is generally thought to be mediated exclusively by lymphocytes such as memory T and B cells. However, enhanced innate immune responses caused by a previous infection increase protection against reinfection suggesting the presence of innate immunological memory. Here, we describe 3,811 ATF7 binding sites in mouse peritoneal macrophages, and 95% of the ATF7 signals in wild-type macrophages are lost in ATF7 knockout macrophages. ATF7 suppresses a group of innate-immunity genes in macrophage by recruiting H3K9 dimethyltransferase G9a. TLR ligands induce ATF7 phosphorylation, leading to release of ATF7 from chromatin and reduction in H3K9me2 level. Partially disrupted chromatin structure and increased basal expression on target genes are maintained for a long period, increasing resistance pathogens. Therefore we speculate ATF7 is important factor in controlling innate immunological memory. This series contains one set of whole genome ChIP-chip data and 2 sets of promoter array ChIP-chip data. For all sample, we use three IP .CEL files and three WCE .CEL files (they are triplicated experiments) to make one profile.

2015-08-31 | E-GEOD-71112 | biostudies-arrayexpress

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