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Expression data from Drosophila melanogaster err mutant animals vs. wild type animals at a mid-second instar larval time

ABSTRACT: Cancer cells utilize a unique form of aerobic glycolysis, called the Warburg effect, to efficiently produce the macromolecules required for proliferation. Here we show that a metabolic program related to the Warburg effect is used during normal Drosophila development and regulated by the fly ortholog of the Estrogen-Related Receptor (ERR) family of nuclear receptors. dERR null mutants die as second instar larvae with abnormally low ATP levels, diminished triacylglyceride stores, and elevated levels of circulating sugars. Metabolomic profiling revealed that the pathways affected in these mutants correspond to those used in the Warburg effect. The expression of active dERR protein in mid-embryogenesis triggers a coordinate switch in gene expression that drives a metabolic program supporting the dramatic growth that occurs during larval development. This study suggests that mammalian ERR family members may promote cancer by directing a metabolic state that supports proliferation.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE23336 | GEO | 2011/02/02

SECONDARY ACCESSION(S): PRJNA131219

REPOSITORIES: GEO

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Expression data from Drosophila melanogaster err mutant animals vs. wild type animals at a mid-second instar larval time

Project description:Cancer cells utilize a unique form of aerobic glycolysis, called the Warburg effect, to efficiently produce the macromolecules required for proliferation. Here we show that a metabolic program related to the Warburg effect is used during normal Drosophila development and regulated by the fly ortholog of the Estrogen-Related Receptor (ERR) family of nuclear receptors. dERR null mutants die as second instar larvae with abnormally low ATP levels, diminished triacylglyceride stores, and elevated levels of circulating sugars. Metabolomic profiling revealed that the pathways affected in these mutants correspond to those used in the Warburg effect. The expression of active dERR protein in mid-embryogenesis triggers a coordinate switch in gene expression that drives a metabolic program supporting the dramatic growth that occurs during larval development. This study suggests that mammalian ERR family members may promote cancer by directing a metabolic state that supports proliferation. Drosophila larvae were staged at a mid-second instar time point and hand sorted for developmental progression. Individual pools of isogenic animals were collected for each replicate. Three replcates were assayed for each genotype. The two genotypes assayed were a control wild type strain (w1118) and a transheteroallelic combination of err mutant alleles (err1/err2). Labled RNA was then hybridized onto Affymetrix microarrays.

2011-02-02 | E-GEOD-23336 | biostudies-arrayexpress

The Drosophila Hypoxia-inducible factor 1-alpha is required to establish the larval glycolytic program

Project description:The rapid growth that occurs during Drosophila larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes encoding enzymes in carbohydrate metabolism. The resulting metabolic program exhibits hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports growth. To date, the only factor known to activate the larval glycolytic program is the Drosophila Estrogen-Related Receptor (dERR). However, dERR is dynamically regulated during the onset of this metabolic switch, indicating that other factors must be involved. Here we discover that Sima, the Drosophila ortholog of Hif1α, is also essential for establishing the larval glycolytic program. Using a multi-omics approach, we demonstrate that Sima mutants fail to properly activate aerobic glycolysis and die during larval development with metabolic defects that mimic those observed in dERR mutants. Moreover, we demonstrate that dERR and Sima/Hif1α stabilize one another, as loss either transcription factor results in loss of the other. Considering that the mammalian homologs of ERR and Hif1α also stabilize one another through heterodimer formation, our findings establish the fly as a powerful genetic model for studying the interaction between these two key metabolic regulators.

2024-12-12 | GSE284097 | GEO

Quantitative Analysis of ERR gamma-driven pancreatic acinar cell transcriptome

Project description:The goal of this study is to compare NGS-derived pancreatic acinar cell-based transcriptome profiling (RNA-seq) to evaluate ERR gamma-driven transcriptional program

2020-11-19 | GSE161757 | GEO

The Drosophila Estrogen-Related Receptor acts within the larval fat body to promote triglyceride storage

Project description:Members of the Estrogen-Related Receptor (ERR) family of nuclear receptors (NR) serve a key role in coordinating triglyceride (TAG) accumulation with juvenile growth and development. In both insects and mammals, loss of ERR activity disrupts (TAG) storage during the post-embryonic growth phase, with loss-of-function mutations in mouseErraandDrosophila melanogaster dERRinducing a lean phenotype. However, the role of insect ERRs in controlling TAG accumulation remains poorly understood, as previous multiomic studies largely relied on whole animal analyses. Here we address this shortcoming by using tissue-specific approaches to determine how dERR regulates lipid metabolism within theDrosophilalarval fat body. We found that dERR autonomously promotes TAG accumulation within fat body cells by regulating expression of genes involved in glycolysis, the pentose phosphate pathway, lipid synthesis, andb-oxidation. As an extension of these results, we not only discovered thatdERRmutant fat bodies exhibit decreased expression of known HNF4 target genes but also found that dHNF4 activity is decreased indERRmutants. Overall, our findings indicate that dERR plays a multifaceted role in the larval fat body to coordinate lipid storage with developmental growth and hint at a conserved mechanism by which ERR and HNF4 homologs coordinately regulate metabolic gene expression

2024-08-02 | GSE273774 | GEO

Quantitative analysis of ERR gamma conditional knock-out (cKO) acinar cell transcriptome

Project description:The goal of this study is to compare NGS-derived pancreatic acinar cell transcriptome profiling (RNA-seq) to analyze the alteration of transcriptional program depending on ERR gamma expression.

2021-08-08 | GSE181529 | GEO

Rhizobium sp. ERR 942 isolate:ERR 942

Project description:Rhizobium sp. ERR 942 isolate:ERR 942 Genome sequencing and assembly

| PRJNA536631 | ENA

Rhizobium sp. ERR 922 isolate:ERR 922

Project description:Rhizobium sp. ERR 922 isolate:ERR 922 Genome sequencing and assembly

| PRJNA536632 | ENA

Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

Project description:Cardiac metabolic dysfunction is a hallmark of heart failure. Estrogen related receptors ERRalpha and ERRgamma are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential theraputic intervention for heart failure. However, in vivo studies demonstrating the potential utility of ERR agonists for heart failure treatment are lacking, as compounds with pharmackinetics appropriate for in vivo use have not been available. Using a structure-based design approach, we designed and synthesized two structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915), which significantly improved ejection fraction, ameliorated fibrosis and increased survival associated with pressure overload-induced heart failure without affecting cardiac hypertrophy. Mechanistically, a broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particulary genes involved in fatty acid metabolism and mitochondrial function. Using both in vitro and in vivo genetic dependency experiments, we show that ERRgamma is the main mediatorof ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. Additionally, ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocyte. In summary, ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced heart failure in vivo. Our results provide direct pharmacological evidence supporting the further in vivo development of ERR agonists as novel heart failure theraputics.

2024-01-01 | GSE241075 | GEO

Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

2023-11-21 | GSE239912 | GEO

Integrated multi-omics analysis of adverse cardiac remodeling and metabolic inflexibility upon ErbB2 and ERR⍺ deficiency

Project description:Functional oncogenic links between ErbB2 and ERR⍺ in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERR⍺ also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. Using integrated phosphoproteomic, transcriptomic and metabolic profiling, we uncovered molecular mechanisms associated with the adverse remodeling of cardiac functions in mice with combined attenuation of ErbB2 and ERR⍺ activity. Genetic disruption of both effectors results in profound effects on cardiomyocyte architecture, inflammatory response and metabolism, the latter leading to a decrease in fatty acyl-carnitine species further increasing the reliance on glucose as a metabolic fuel, a hallmark of failing hearts. Furthermore, integrated omics signatures of ERR⍺ loss-of-function and doxorubicin treatment exhibit reciprocal features of chemotherapeutic cardiotoxicity. These findings thus reveal potential cardiovascular risks in discrete combination therapies in the treatment of breast and other cancers.

2022-09-19 | GSE199150 | GEO

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