Transcriptomics of specific activation of the Integrated Stress Response activation in ATF4 WT and ATF4 KO cells
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ABSTRACT:
PROVIDER: PRJNA1142488 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30055448_1.fastq.gz | Fastqsanger.gz | |||
| SRR30055448_2.fastq.gz | Fastqsanger.gz | |||
| SRR30055449_1.fastq.gz | Fastqsanger.gz | |||
| SRR30055449_2.fastq.gz | Fastqsanger.gz | |||
| SRR30055450_1.fastq.gz | Fastqsanger.gz |
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Project description:The integrated stress response (ISR) is a central signaling pathway induced by a variety of insults, but how its outputs contribute to downstream physiological effects across diverse cellular contexts remains unclear. Using a synthetic tool, we specifically and tunably activated the ISR and performed multi-omics profiling to define the core modules elicited by this response in the absence of co-activation of parallel pathways commonly induced by pleiotropic stressors. We found that the ISR can elicit time- and dose-dependent gene expression changes that cluster into four modules with ATF4 driving only a small but fast and sensitive module that includes many amino acid metabolic enzymes. We showed that ATF4 was required to reroute carbon utilization towards amino acid synthesis derived both from glucose and reductive carboxylation of glutamine and away from the tricarboxylic acid cycle and fatty acid biogenesis revealing a new role for ATF4 in modulating cellular energetics. We also discovered an ATF4-independent reorganization of cellular lipids that promotes triglycerides synthesis and accumulation of lipid droplets that was essential for cell survival. Together, we demonstrate that a minimal ISR-inducing system is sufficient to trigger formation of two distinct cellular structures, stress granules and lipid droplets, and a previously unappreciated metabolic state.
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Project description:Oxidative stress is pathogenic in neurological diseases including stroke. The identity of oxidative stress-inducible transcription factors and their role(s) in propagating the death cascade are poorly understood. Microarray analysis of neurons undergoing oxidative stress showed significant induction of prodeath genes. These genes have been shown to be regulated by the bZip transcription factor, ATF4. ATF4 protein localized to the promoter of a putative death gene in neurons in vitro and in vivo. Germline deletion of ATF4 in neurons resulted in a reduction in oxidative stress-induced gene expression and resistance to oxidative death. ATF4 knockout mice experienced significantly smaller infarcts and improved behavioral recovery as compared to wild-type mice subjected to the same reductions in blood flow in a rodent model of stroke. ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Restoration of ATF4 protein in knockout neurons was sufficient to restore sensitivity to oxidative death and to reaccelerate loss of glutathione. Together, these findings establish ATF4 as a redox-regulated, pro-death transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo. Keywords: ATF4, oxidative stress, gene expression, neuroprotection, stroke WT and ATF4 KO embryonic neurons were studied. Untreated neurons (no=8 per genotype) and neurons challenged with oxidative stress with the glutamate homolog homocysteate (HCA, no=4 per genotype) were studied, for a total of 24 samples.
2010-06-25 | E-GEOD-10470 | biostudies-arrayexpress
Project description:Cells rapidly and extensively remodel their transcriptome in response to stress to restore homeostasis, but the underlying mechanisms are not fully understood. Here we characterize the dynamic changes in transcriptome, epigenetics, and 3D genome organization during the integrated stress response (ISR). ISR induction triggers widespread transcriptional changes within 6 hours, coinciding with increased binding of ATF4, a key transcriptional effector. Notably, ATF4 binds to hundreds of genes even under non-stress conditions, priming them for stronger activation upon stress. The transcriptional changes during ISR do not rely on increased H3K27 acetylation, chromatin accessibility, or rewired enhancer-promoter looping. Instead, ATF4-mediated gene activation is linked to the redistribution of CEBPγ from non-ATF4 sites to a subset of ATF4-bound regions, likely by forming an ATF4/CEBPγ heterodimer. CEBPγ preferentially targets the sites pre-occupied by ATF4, as well as genomic regions exhibiting a unique higher-order chromatin structure signature. Thus, the transcriptional responses during ISR are largely pre-wired by intrinsic chromatin properties. These findings provide novel insights into transcriptional remodeling during ISR with broader implications for other stress responses. Through the IP-MS experiments, we determined the proteins that interacted with ATF4 and their change during ISR.
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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
Project description:Upon encountering stress, cells need to rapidly and extensively remodel their transcriptome to restore homeostasis and ensure survival. However, the molecular mechanisms underlying stress-induced transcriptional remodeling are not well understood. In this study, we employed multi-omics approaches to comprehensively profile the changes in transcriptome, epigenetic landscapes, and 3D genome organization during the integrated stress response (ISR), a conserved cellular pathway activated by diverse stress stimuli. Our findings reveal that widespread transcriptional changes occur 4-6 hours after the induction of ISR, coinciding with the genome-wide binding of key transcriptional effector ATF4. Notably, while ATF4 binds to most of its target genes only upon ISR activation, it also occupies the promoters of hundreds of genes under non-stress conditions, priming them for enhanced transcriptional activation in response to stress signals. We further demonstrate that ATF4-mediated gene activation does not rely on traditional transcriptional regulatory mechanisms, such as increased H3K27 acetylation, chromatin accessibility, or remodeling of enhancer-promoter loops. Instead, our data suggest that the nuclear localization of ATF4 induces a pronounced genomic redistribution of transcriptional factor CEBP-γ, from non-ATF4 sites to a subset of ATF4-bound regions, where it collaborates with ATF4 to elicit transcriptional activation. The combined occupancy of ATF4 and CEBP-γ ultimately dictates the transcriptional outcomes during ISR. Interestingly, the preferred binding sites of CEBP-γ in response to stress are not determined by the strength of the CEBP-γ or ATF4 motifs, but rather by the higher-order chromatin architecture surrounding the binding sites. These findings provide novel insights into the molecular mechanisms that govern the rapid and efficient transcriptional remodeling during ISR, with potential implications for other stress responses.
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Project description:Upon encountering stress, cells need to rapidly and extensively remodel their transcriptome to restore homeostasis and ensure survival. However, the molecular mechanisms underlying stress-induced transcriptional remodeling are not well understood. In this study, we employed multi-omics approaches to comprehensively profile the changes in transcriptome, epigenetic landscapes, and 3D genome organization during the integrated stress response (ISR), a conserved cellular pathway activated by diverse stress stimuli. Our findings reveal that widespread transcriptional changes occur 4-6 hours after the induction of ISR, coinciding with the genome-wide binding of key transcriptional effector ATF4. Notably, while ATF4 binds to most of its target genes only upon ISR activation, it also occupies the promoters of hundreds of genes under non-stress conditions, priming them for enhanced transcriptional activation in response to stress signals. We further demonstrate that ATF4-mediated gene activation does not rely on traditional transcriptional regulatory mechanisms, such as increased H3K27 acetylation, chromatin accessibility, or remodeling of enhancer-promoter loops. Instead, our data suggest that the nuclear localization of ATF4 induces a pronounced genomic redistribution of transcriptional factor CEBP-γ, from non-ATF4 sites to a subset of ATF4-bound regions, where it collaborates with ATF4 to elicit transcriptional activation. The combined occupancy of ATF4 and CEBP-γ ultimately dictates the transcriptional outcomes during ISR. Interestingly, the preferred binding sites of CEBP-γ in response to stress are not determined by the strength of the CEBP-γ or ATF4 motifs, but rather by the higher-order chromatin architecture surrounding the binding sites. These findings provide novel insights into the molecular mechanisms that govern the rapid and efficient transcriptional remodeling during ISR, with potential implications for other stress responses.
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