Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1240436 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32814047_1.fastq.gz | Fastqsanger.gz | |||
| SRR32814047_2.fastq.gz | Fastqsanger.gz | |||
| SRR32814048_1.fastq.gz | Fastqsanger.gz | |||
| SRR32814048_2.fastq.gz | Fastqsanger.gz | |||
| SRR32814049_1.fastq.gz | Fastqsanger.gz |
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Project description:Huntington’s Disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional deregulation and altered energy metabolism have been implicated in HD pathogenesis. We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1a, a transcriptional coactivator that regulates several metabolic processes including mitochondrial biogenesis and respiration. Mutant huntingtin represses PGC-1a gene transcription by associating with the promoter and interfering with the CREB/TAF4-dependent transcriptional pathway critical for the regulation of PGC-1a gene expression. Crossbreeding of PGC-1a knockout mice with HD knock-in mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice. Importantly, expression of PGC-1a partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons. Moreover, lentiviral-mediated delivery of PGC-1a in the striatum provides neuroprotection in the transgenic HD mice. These studies suggest a key role for PGC-1a in the control of energy metabolism in the early stages of HD pathogenesis. Keywords: PGC-1a, striatum
2006-10-05 | GSE5786 | GEO
Project description:The peroxisome proliferator-activated receptor c coactivator 1 (PGC-1) proteins are key regulators of cellular bioenergetics and are accordingly expressed in tissues with a high energetic demand. For example, PGC-1a and PGC-1b control organ function of brown adipose tissue, heart, brain, liver and skeletal muscle. Surprisingly, despite their prominent role in the control of mitochondrial biogenesis and oxidative metabolism, expression and function of the PGC-1 coactivators in the retina, an organ with one of the highest energy demands per tissue weight, are completely unknown. Moreover, the molecular mechanisms that coordinate energy production with repair processes in the damaged retina remain enigmatic. In the present study, we thus investigated the expression and function of the PGC-1 coactivators in the healthy and the damaged retina. We show that PGC-1a and PGC-1b are found at high levels in different structures of the mouse retina, most prominently in the photoreceptors. Furthermore, PGC-1a knockout mice suffer from a striking deterioration in retinal morphology and function upon detrimental light exposure. Gene expression studies revealed dysregulation of all major pathways involved in retinal damage and apoptosis, repair and renewal in the PGC-1a knockouts. The light-induced increase in apoptosis in vivo in the absence of PGC-1a was substantiated in vitro, where overexpression of PGC-1a evoked strong anti-apoptotic effects. Finally, we found that retinal levels of PGC-1 expression are reduced in different mouse models for retinitis pigmentosa. We demonstrate that PGC-1a is a central coordinator of energy production and, importantly, all of the major processes involved in retinal damage and subsequent repair. Together with the observed dysregulation of PGC-1a and PGC-1b in retinitis pigmentosa mouse models, these findings thus imply that PGC-1a might be an attractive target for therapeutic approaches aimed at retinal degeneration diseases.
2016-04-15 | GSE80265 | GEO
Project description:Metastatic bladder cancer is a malignant tumor with high metastatic potential. The etiology and molecular mechanism are still not fully understood. This study aimed to investigate the effect of PGC-1 α siRNA delivered by liposomal nanoparticles on bladder cancer cells, in order to reveal its mechanism in tumor cell reprogramming and energy metabolism regulation. Through transcriptome, proteome and metabolomics, we found that PGC-1 α was significantly upregulated in bladder cancer metastasis, and constructed a nanoparticle delivery system for efficient delivery of PGC-1 α siRNA. In vitro results showed that PGC-1 α silencing inhibited mitochondrial biogenesis and energy metabolism in bladder cancer cells, and interfered with the extranuclear transport of mRNA. Metabolomic analysis further confirmed the changes in cellular metabolism, especially the effects of glycolysis and tricarboxylic acid cycle pathways. The in vivo model further verified that si-pgc-1 α LNP could significantly reduce the number of lung metastases of metastatic bladder cancer, showing anti metastatic potential. These findings reveal the important role of PGC-1 α in the regulation of energy metabolism and metastasis of bladder cancer cells, and provide a new strategic direction for the treatment of metastatic bladder cancer.
2025-03-22 | PXD062153 |
Project description:Huntington's Disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional deregulation and altered energy metabolism have been implicated in HD pathogenesis. We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1a, a transcriptional coactivator that regulates several metabolic processes including mitochondrial biogenesis and respiration. Mutant huntingtin represses PGC-1a gene transcription by associating with the promoter and interfering with the CREB/TAF4-dependent transcriptional pathway critical for the regulation of PGC-1a gene expression. Crossbreeding of PGC-1a knockout mice with HD knock-in mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice. Importantly, expression of PGC-1a partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons. Moreover, lentiviral-mediated delivery of PGC-1a in the striatum provides neuroprotection in the transgenic HD mice. These studies suggest a key role for PGC-1a in the control of energy metabolism in the early stages of HD pathogenesis. Experiment Overall Design: Total RNA was extracted from striata of 3 pgc1 KO mice and 3 littermate controls using the RNeasy Mini Kit (Qiagen) according to manufacturer's protocol. Samples were analyzed using RNA 6000 Nano LabChip kit on a 2100 Bioanalyzer (Agilent Technologies) to ensure integrity of RNA.
2007-11-13 | E-GEOD-5786 | biostudies-arrayexpress
Project description:Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation and reactive oxygen species scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1a is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1a activity. To test this model for the first time, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1a (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1a is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy demonstrated that PGC-1a is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1a is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1a nor mitochondrial biogenesis in skeletal muscle are required for the metabolic benefits of CR.
2012-02-04 | GSE34773 | GEO
Project description:The following abstract from the submitted manuscript describes the major findings of this work. The metabolic development of high energy-utilizing organs such as the heart involves mitochondrial proliferation at birth followed by a maturation process during the postnatal period. Conditional gene targeting was used in mice to explore the role of the PPARgamma coactivator 1 (PGC-1) coactivators during postnatal development and in adult heart. Marked mitochondrial derangements were observed in hearts of PGC-1a/b-deficient mice during the postnatal period, including fragmentation and elongation associated with the development of a lethal cardiomyopathy. The expression of multiple genes involved in mitochondrial fusion and fission was downregulated in hearts of PGC-1a/b-deficient mice. PGC-la was shown to activate transcription of the mitofusin 1 (Mfn1) gene by coactivating the estrogen-related receptor a (ERRa) upon a highly conserved element. Surprisingly, PGC-1a/b deficiency did not alter cardiac function or general mitochondrial density and myocyte distribution in adult heart. However, transcriptional profiling and mitochondrial function studies demonstrated that the PGC-1 coactivators are required for full respiratory capacity and high level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial energy transduction and oxidative phosphorylation pathways in adult heart. These results unveil distinct developmental stage-specific transcriptional programs involved in the maturation and maintenance of mitochondria. RNA from five PGC-1a-/- and five PGC-1a-/-bf/f/MerCre mice was analyzed.
2014-01-13 | E-GEOD-43798 | biostudies-arrayexpress
Project description:Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation and reactive oxygen species scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1a is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1a activity. To test this model for the first time, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1a (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1a is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy demonstrated that PGC-1a is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1a is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1a nor mitochondrial biogenesis in skeletal muscle are required for the metabolic benefits of CR. Control (FLOX) and PGC-1a skeletal muscle specific knock out (MKO) mice were placed on a control diet [C] or a calorie restriction diet [CR] for 12 weeks. RNA was isolated from TA/EDL muscles for microarray analysis. The following numbers of mice were analyzed from each group: C FLOX: n = 6; C MKO: n = 7; CR FLOX: n = 6; CR MKO: n = 7. Mice were mixed C57/BL6 and 129 background.
2012-02-04 | E-GEOD-34773 | biostudies-arrayexpress
Project description:The brain is a high energy tissue, and the cell types of which it is comprised are distinct in function and in metabolic requirements. The transcriptional co-activator PGC-1a is a master regulator of mitochondrial function and is highly expressed in the brain; however, its cell-type-specific role in regulating metabolism has not been well established. Here, we show that PGC-1a is responsive to aging and that expression of the neuron-specific PGC-1a isoform allows for specialization in metabolic adaptation. Transcriptional profiles of the cortex from male mice show an impact of age on immune, inflammatory, and neuronal pathways and a highly integrated metabolic response associated with decreased expression of PGC-1a. Proteomic analysis confirms age-related changes in metabolism and further shows changes in ribosomal and RNA splicing pathways. We show that neurons express a specialized PGC-1a isoform that becomes active during differentiation from stem cells and is further induced during the maturation of isolated neurons. Neuronal but not astrocyte PGC-1a responds robustly to inhibition of the growth-sensitive kinase GSK3b, where the brain-specific promoter-driven dominant isoform is repressed. The GSK3b inhibitor lithium broadly reprograms metabolism and growth signaling, including significantly lowering expression of mitochondrial and ribosomal pathway genes and suppressing growth signaling, which are linked to changes in mitochondrial function and neuronal outgrowth. In vivo, lithium treatment significantly changes the expression of genes involved in cortical growth, endocrine, and circadian pathways. These data place the GSK3b/PGC-1a axis centrally in a growth and metabolism network directly relevant to brain aging.
2025-02-07 | GSE246478 | GEO
Project description:This study aims to explore the effect of PGC-1 α siRNA delivered by liposomal nanoparticles on cancer cells through transcriptome, proteome and metabolome technologies, so as to reveal its regulatory effect on cancer cell reprogramming and energy metabolism, so as to provide clues for the molecular mechanism of the treatment of metastatic bladder cancer.
2025-03-22 | PXD062155 |
Project description:Mechanisms to coordinately regulate oxidative metabolism and glucose transport into cells are not well described. In muscle and fat, insulin mobilizes GLUT4 glucose transporters to the cell surface in part by stimulating the site-specific endoproteolytic cleavage of TUG proteins. Here, we show that the TUG C-terminal cleavage product enters the nucleus, binds the transcriptional 30 regulators PGC-1a and PPARg, and increases oxidative metabolism, thermogenic protein expression, and energy expenditure. The PPARg2 Pro12Gly polymorphism, which confers reduced diabetes risk, enhances TUG binding. The TUG cleavage product stabilizes PGC-1a, so that both proteins are susceptible to an Ate1 arginyltransferase -dependent degradation mechanism. We conclude that TUG cleavage coordinates energy expenditure with glucose 35 uptake, and that alterations in this pathway may contribute to metabolic disease.
2020-07-23 | GSE134846 | GEO