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Genome-wide analysis of ATF4 binding in histidinol-treated cells

ABSTRACT: Activating Transcription Factor 4 (ATF4) is a transcription factor induced by the integrated stress response (ISR). This experiment is a genome-wide occupancy profiling of ATF4 in human HAP1 cells. HAP1 is a near-haploid human cell line that was derived from KBM-7 cells isolated from a patient with Chronic Myelogenous Leukemia. We induced ATF4 expression by mimicking amino acid starvation with the drug histidinol. We identified peaks of ATF4 binding using three independent antibodies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE69304 | GEO | 2015/08/28

SECONDARY ACCESSION(S): PRJNA285118

REPOSITORIES: GEO

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Genome-wide analysis of ATF4 binding in histidinol-treated cells

Project description:Activating Transcription Factor 4 (ATF4) is a transcription factor induced by the integrated stress response (ISR). This experiment is a genome-wide occupancy profiling of ATF4 in human HAP1 cells. HAP1 is a near-haploid human cell line that was derived from KBM-7 cells isolated from a patient with Chronic Myelogenous Leukemia. We induced ATF4 expression by mimicking amino acid starvation with the drug histidinol. We identified peaks of ATF4 binding using three independent antibodies. Examination of ATF4 binding in HAP1 cells treated with 2 mM histidinol for 24 hours.

2015-08-28 | E-GEOD-69304 | biostudies-arrayexpress

RNA-Seq experiment to identify genes regulated by ATF4

Project description:Activating Transcription Factor 4 (ATF4) is a transcription factor induced by the integrated stress response (ISR). This experiment is a genome-wide profiling of ATF4-dependent RNA expression in human HAP-1 cells. HAP-1 is a near-haploid human cell line that was derived from KBM-7 cells isolated from a patient with Chronic Myelogenous Leukemia. We analyzed WT and ATF4 KO cells. We induced ATF4 expression by mimicking amino acid starvation with the drug histidinol. RNA expression profiles were generated for WT and ATF4 KO HAP1 cells. ATF4 genes were mutated using Cas9 genome editing technology. Amino acid starvation was mimicked by treating WT and ATF4 KO cells with 2 mM histidinol for 24 hours, which increases ATF4 expression.

2015-08-28 | E-GEOD-69308 | biostudies-arrayexpress

RNA-Seq experiment to identify genes regulated by ATF4

2015-08-28 | GSE69308 | GEO

RNAseq Analysis of TP53+/+ and TP53-/- HCT116 colon carcinoma cell lines after treatment with p53 or ATF4-activating compounds

Project description:We examined the gene expression changes resulting from treatment of either "wild-type" or "p53-deficient" human cell lines with compounds known to activate either p53 (nutlin-3A,etoposide) or the integrated stress response (ISR) transcription factor ATF4 (histidinol,tunicamycin)

2022-08-20 | GSE211244 | GEO

Microarray expression data of NCI-H1975 cells treated with osimertinib, alpelisib, or combination of these in the presence or absence of L-histidinol.

Project description:Oncogenic signals often activate abnormal proliferation, while simultaneously activate stress-adaptive mechanisms such as the integrated stress response (ISR) to ensure rapid growth under intrinsic and extrinsic stress conditions. In this study, we investigated the involvement of EGFR-PI3K pathway in the regulation of ISR in EGFR-mutant NSCLC cell lines under amino acid deprivation. We found that the third generation EGFR inhibitor osiemrtinib suppressed induction of activation transcription factor 4 (ATF4), the key ISR effector, in EGFR mutant cells, while the effect was to a less extent in cells harboring PIK3CA-co-alteration. PI3K inhibitors including P110a-specific inhibitor alpelicib markedly suppress ATF4 induction in PIK3CA-mutant cell lines. To further explore the role of EGFR-PI3K, transcriptome analysis was performed in EGFR- and PIK3CA-mutated NCI-H1975 cells treated with osimertinib, alpelisib, or combination of these in the absence or presence of histidyl-tRNA inhibitor L-histidinol (His), mimicking amino acid deprived conditions. Among His-induced genes, either osimertinib or alpelisib partially, but the combination dramatically suppressed a cluster of genes targeted by ATF4. Furthermore, combination of osimertinib and alpelisib increased apoptotic cells under amino acid deprived conditions. These results indicate that oncogenic EGFR-PI3K pathway contributes to cellular adaptation to stress conditions through ATF4. We used microarrays to identify genes whose expression is up- or down-regulated by inhibition of EGFR, PI3K, or both under amino acid deprivation.

2023-03-22 | GSE216508 | GEO

Genome wide binding of ATF4 and CEBPG bZIP transcription factors in MEFs under amino acid deprived (AAD) conditions

Project description:The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBPÎ³:ATF4 heterodimers, but not C/EBPÎ²:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBPÎ³ and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBPÎ² and CHOP were largely dispensable for induction of stress genes. Cebpgâ/â MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpgâ/â mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPÎ³-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpgâ/â mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBPÎ³ as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. Evaluation of genomic binding of 2 bZIP transcription factors under amino acid deprivation conditions in mouse embryonic fibroblasts

2015-11-19 | E-GEOD-75165 | biostudies-arrayexpress

Whole genome expression data from WT, Atf4-/-, and Cebpg-/- MEFs under normal and amino acid deprived (AAD) growth conditions

Project description:The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBPÎ³:ATF4 heterodimers, but not C/EBPÎ²:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBPÎ³ and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBPÎ² and CHOP were largely dispensable for induction of stress genes. Cebpgâ??/â?? MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpgâ??/â?? mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPÎ³-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpgâ??/â?? mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBPÎ³ as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. WT, Atf4-/-, and Cebpg-/- MEFs (passage 3) were cultured under normal and AAD conditions. RNA from each treatment condition was collected in triplicate for hybrization on Affymetrix Mouse Genome 430 2.0 microarrays.

2015-11-19 | E-GEOD-75150 | biostudies-arrayexpress

Plasticity of the Mammalian Integrated Stress Response [atf4]

Project description:Decreased nucleotide exchange activity of the eukaryotic translation initiation factor eIF2B coupled with increased phosphorylation of eIF2alpha (eIF2alpha-p) is a hallmark of the “canonical” integrated stress response (c-ISR). In mammals, however, it is unclear whether decreased eIF2B activity in absence of alterations in eIF2alpha-p which occurs in human disease including leukodystrophies, is synonymous to c-ISR. Herein, we describe a previously unknown mechanism of adaptation to decreased eIF2B activity, distinct from c-ISR, which we term “split” ISR (s-ISR). We demonstrate that s-ISR comprises translation reprogramming of only a subset of c-ISR mRNA targets which is accompanied by distinct transcriptomes. In contrast to c-ISR, s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (e.g., PCK2), resulting in metabolic adaptations to maintain cellular bioenergetics under conditions of low eIF2B activity. Overall, these data demonstrate hitherto-unappreciated plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of increased eIF2-p, activates an eIF4E/ATF4/PCK2 axis to maintain energy homeostasis.

2025-01-22 | GSE268127 | GEO

Global proteome analysis of ATF4 targets during ER stress.

Project description:Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. To identify ATF4 target genes that mediate the ISR outcome and to get insight into its mechanism of action in PCa, we performed global proteomic expression profiling in parallel with transcriptomic expression profiling. These data show that ATF4 regulates important metabolic pathways in PCa cells.

2019-07-22 | PXD012858 | Pride

ISR target genes revealed by comprehensive microarray network study using Perk -/-, Atf4 -/-, eIF2a S51A mutant, Fv2E-PERK

Project description:To identify the target genes of integrated stress reponse (ISR), we have employed whole genome microarray expression in MEF cells. ISR gene setimation under ER stress condition using Perk -/-, Atf4 -/-, eIF2a S51A mutant, Fv2E-PERK MEF cells

2015-09-01 | E-GEOD-49598 | biostudies-arrayexpress

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