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Analysis of gene expression changes induced in wild-type or Atf6a-/- mice by treatment with tunicamycin for 8h

ABSTRACT: Protein misfolding stress in the endoplasmic reticulum (ER) leads to dysregulation of lipid metabolism in the liver, and ER stress is associated with human diseases that are accompanied by hepatic lipid accumulation, including obesity, alcoholism, and viral hepatitis; yet the pathways leading from ER stress to the regulation of lipid metabolism are poorly understood. Working exclusively in vivo, we used a “bottom-up” approach to infer pathways in the genetic regulation of lipid metabolism by the UPR. We used a functional genomics to link gene expression patterns taken from microarray data to the severity and persistence of ER stress, using mice lacking the UPR signaling molecule ATF6α. This approach revealed that functionally related genes clustered into a small number of distinct expression profiles, and that lipid oxidation and efflux were targets for coordinated transcriptional suppression during ER stress.Our results establish a framework for hepatic gene regulation during ER stress.

ORGANISM(S): Mus musculus

PROVIDER: GSE48932 | GEO | 2013/09/04

SECONDARY ACCESSION(S): PRJNA212335

REPOSITORIES: GEO

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Analysis of gene expression changes induced in wild-type or Atf6a-/- mice by treatment with tunicamycin for 8h

Project description:Protein misfolding stress in the endoplasmic reticulum (ER) leads to dysregulation of lipid metabolism in the liver, and ER stress is associated with human diseases that are accompanied by hepatic lipid accumulation, including obesity, alcoholism, and viral hepatitis; yet the pathways leading from ER stress to the regulation of lipid metabolism are poorly understood. Working exclusively in vivo, we used a “bottom-up” approach to infer pathways in the genetic regulation of lipid metabolism by the UPR. We used a functional genomics to link gene expression patterns taken from microarray data to the severity and persistence of ER stress, using mice lacking the UPR signaling molecule ATF6α. This approach revealed that functionally related genes clustered into a small number of distinct expression profiles, and that lipid oxidation and efflux were targets for coordinated transcriptional suppression during ER stress.Our results establish a framework for hepatic gene regulation during ER stress. Atf6a-/- or +/+ mice of variable age and gender were injected intraperitoneally with 2 mg/kg tunicamycin or vehicle. 3 separate mice were used in each group. 8h after injection, mice were sacrificed and total RNA was prepared from resected livers.

2013-09-04 | E-GEOD-48932 | biostudies-arrayexpress

Analysis of gene expression changes induced in wild-type or Atf6a-/- mice by treatment with tunicamycin for 34h

Project description:Protein misfolding stress in the endoplasmic reticulum (ER) leads to dysregulation of lipid metabolism in the liver, and ER stress is associated with human diseases that are accompanied by hepatic lipid accumulation, including obesity, alcoholism, and viral hepatitis; yet the pathways leading from ER stress to the regulation of lipid metabolism are poorly understood. Working exclusively in vivo, we used a “bottom-up” approach to infer pathways in the genetic regulation of lipid metabolism by the UPR. We used a functional genomics to link gene expression patterns taken from microarray data to the severity and persistence of ER stress, using mice lacking the UPR signaling molecule ATF6α. This approach revealed that functionally related genes clustered into a small number of distinct expression profiles, and that lipid oxidation and efflux were targets for coordinated transcriptional suppression during ER stress.Our results establish a framework for hepatic gene regulation during ER stress. Atf6a-/- or +/+ mice of variable age and gender were injected intraperitoneally with 1 mg/kg tunicamycin or vehicle. 3 separate mice were used in each group. 34h after injection, mice were sacrificed and total RNA was prepared from resected livers.

2013-09-04 | E-GEOD-48935 | biostudies-arrayexpress

Analysis of gene expression changes induced in wild-type or Atf6a-/- mice by treatment with tunicamycin for 34h

2013-09-04 | GSE48935 | GEO

ER stress inhibits liver fatty acid oxidation while unmitigated stress leads to anorexia-induced lipolysis and both liver and kidney steatosis

Project description:The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation are unclear, including which pathways contribute to the phenotype in each organ. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver, but not the kidney; while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress.

2017-06-23 | MTBLS472 | MetaboLights

Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

Project description:Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation (ChIP) analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.

2020-04-24 | GSE131146 | GEO

HERV1-env dependent unfolded protein response activation is a potential initiator of T cell autoreactivity in autoimmune liver disease.

Project description:Here we report Human Endogenous Retrovirus 1 (HERV1-env) induction of endoplasmic reticulum (ER) stress with Unfolded Protein Response (UPR) activation, through its interaction with ATF6.ATF6α up-regulates RORC, STAT3 and TBX21 and induces IL-17A and INF-γ production in Tregs by binding to promoter sequences.

2022-08-02 | GSE135410 | GEO

The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress

Project description:Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK. 14 gene expression arrays, 3 WT control arrays; 3 lsPERK control arrays; 4 WT Treated arrays; 4 lsPERK treated arrays. Comparison of gene expression profiles for treated vs control in wildtype and knock-out.

2012-01-20 | E-GEOD-29929 | biostudies-arrayexpress

Lipid bilayer stress-activated IRE-1 modulates autophagy during endoplasmic reticulum stress

Project description:Metabolic disorders such as obesity and nonalcoholic fatty liver disease (NAFLD) are emerging disorders that affect the global population. One facet of the disorders is attributed to the disturbance of membrane lipid homeostasis. Perturbation of endoplasmic reticulum (ER) homeostasis through changes in membrane phospholipid composition results in activation of the unfolded protein response (UPR) and causes dramatic translational and transcriptional changes in cell. To restore cellular homeostasis, the three highly conserved UPR transducers ATF6, IRE1, and PERK mediate cellular processes upon ER stress. The roles of the UPR in proteostatic stress caused by the accumulation of misfolded protein is well understood but lipid perturbation-induced UPR remains elusive. We found that genetically attenuated PC synthesis in C. elegans causes lipid droplets accumulation if not for the intervention of the UPR program. Transcriptional profiling of lipid perturbation-induced ER stress animals shows a unique subset of genes modulated in an UPR-dependent manner that are unaffected by proteostatic stress. Among these, we identified IRE1-modulated autophagy genes that trigger liberation of free fatty acids from excess lipid droplets suggesting a stress release mechanism by which free fatty acids are rechannelling to restore lipid homeostasis. Considering the important role of lipid homeostasis and how its impairment contributes to the pathologies in metabolic diseases, our data uncovers the indispensable role of a fully functional UPR program in regulating lipid homeostais in the face of chronic ER stress.

2018-10-31 | GSE99763 | GEO

The effect of deficiency of two ATF6 homologues at early developmental stage

Project description:Mammalian ATF6α/β are membrane-bound transcription factors which are activated by endoplasmic reticulum (ER) stress-induced proteolysis to upregulate various ER quality control proteins to maintain the homeostasis of the ER. ATF6α- and ATF6β-single knockout mice develop normally but ATF6α/β-double knockout causes embryonic lethality, the reason for which remains unknown. Here, we showed that medaka fish exhibits the same phenotype regarding the effects of deleting ATF6α, ATF6β, and both. Analyses revealed that ER stress occurred physiologically during early embryonic development, particularly in the brain, otic vesicle and notochord. The absence of transcriptional induction of ER chaperones in ATF6α/β-double knockout blocked notochord development, which was partially rescued by microinjection-mediated overexpression of the major ER chaperone BiP. Thus, ATF6α/β-mediated adjustment of chaperones to the increased demands in the ER is essential for development of the notochord, which synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis.

2013-02-20 | GSE37174 | GEO

Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

Project description:Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress.

2015-05-12 | GSE68718 | GEO

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