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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229595 | 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

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

2024-05-07 | GSE229593 | GEO

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

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

| PRJNA955104 | ENA

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

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

| PRJNA955111 | ENA

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

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

| PRJNA955115 | ENA

A cytoplasmic negative regulator isoform of ATF7 impairs ATF7 and ATF2 phosphorylation and transcriptional activity.

Project description:Alternative splicing and post-translational modifications are processes that give rise to the complexity of the proteome. The nuclear ATF7 and ATF2 (activating transcription factor) are structurally homologous leucine zipper transcription factors encoded by distinct genes. Stress and growth factors activate ATF2 and ATF7 mainly via sequential phosphorylation of two conserved threonine residues in their activation domain. Distinct protein kinases, among which mitogen-activated protein kinases (MAPK), phosphorylate ATF2 and ATF7 first on Thr71/Thr53 and next on Thr69/Thr51 residues respectively, resulting in transcriptional activation. Here, we identify and characterize a cytoplasmic alternatively spliced isoform of ATF7. This variant, named ATF7-4, inhibits both ATF2 and ATF7 transcriptional activities by impairing the first phosphorylation event on Thr71/Thr53 residues. ATF7-4 indeed sequesters the Thr53-phosphorylating kinase in the cytoplasm. Upon stimulus-induced phosphorylation, ATF7-4 is poly-ubiquitinated and degraded, enabling the release of the kinase and ATF7/ATF2 activation. Our data therefore conclusively establish that ATF7-4 is an important cytoplasmic negative regulator of ATF7 and ATF2 transcription factors.

| S-EPMC3156760 | biostudies-literature

ATF7 mediates TNF-?-induced telomere shortening.

Project description:Telomeres maintain the integrity of chromosome ends and telomere length is an important marker of aging. The epidemiological studies suggested that many types of stress including psychosocial stress decrease telomere length. However, it remains unknown how various stresses induce telomere shortening. Here, we report that the stress-responsive transcription factor ATF7 mediates TNF-?-induced telomere shortening. ATF7 and telomerase, an enzyme that elongates telomeres, are localized on telomeres via interactions with the Ku complex. In response to TNF-?, which is induced by various stresses including psychological stress, ATF7 was phosphorylated by p38, leading to the release of ATF7 and telomerase from telomeres. Thus, a decrease of ATF7 and telomerase on telomeres in response to stress causes telomere shortening, as observed in ATF7-deficient mice. These findings give credence to the idea that various types of stress might shorten telomere.

| S-EPMC5961373 | biostudies-literature

BMI1 Maintains the Regulatory T cell Epigenomic Landscape to Prevent Inflammatory Bowel Disease

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

2021-03-31 | GSE171190 | GEO

Myt Transcription Factors Prevent Stress-Response Gene Overactivation to Enable Postnatal Pancreatic β Cell Proliferation, Function, and Survival.

Project description:Although cellular stress response is important for maintaining function and survival, overactivation of late-stage stress effectors cause dysfunction and death. We show that the myelin transcription factors (TFs) Myt1 (Nzf2), Myt2 (Myt1l, Nztf1, and Png-1), and Myt3 (St18 and Nzf3) prevent such overactivation in islet β cells. Thus, we found that co-inactivating the Myt TFs in mouse pancreatic progenitors compromised postnatal β cell function, proliferation, and survival, preceded by upregulation of late-stage stress-response genes activating transcription factors (e.g., Atf4) and heat-shock proteins (Hsps). Myt1 binds putative enhancers of Atf4 and Hsps, whose overexpression largely recapitulated the Myt-mutant phenotypes. Moreover, Myt(MYT)-TF levels were upregulated in mouse and human β cells during metabolic stress-induced compensation but downregulated in dysfunctional type 2 diabetic (T2D) human β cells. Lastly, MYT knockdown caused stress-gene overactivation and death in human EndoC-βH1 cells. These findings suggest that Myt TFs are essential restrictors of stress-response overactivity.

| S-EPMC7278035 | biostudies-literature

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