Effects of Peroxisome proliferator-γ coactivator-1α (PGC-1a) isoform over-expression +/- TNFalpha on hepatocyte gene expression
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PROVIDER: PRJNA548127 | ENA |
REPOSITORIES: ENA
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Project description:PGC-1a is a transcriptional coactivator known to regulate a broad gene program of nutrient and mitochondrial metabolism. Many splice variants of this protein have been identified, but their functions were unknown. This experiment was designed to delineate the downstream targets of two different PGC-1alpha isoforms (PGC-1a1 and PGC-1a4) in hepatocytes, and to determine whether inflammatory signaling (via TNFR activation) modulated these targets Liver is exposed to constantly changing metabolic and inflammatory environments. It must quickly sense and adapt to metabolic need while balancing resources required to protect itself from harmful inflammatory molecules. PGC-1α is a transcriptional coactivator that mediates cellular adaptation to diverse stimuli including inflammation. PGC-1α has a protective role against inflammation in several organs, including brain, heart, kidney, muscle, and liver. However, it is not known how hepatic PGC-1α integrates extracellular signals to mitigate inflammatory outcomes. PGC-1α exists as multiple, alternatively spliced variants whose expression is differentially regulated by different gene promoters. In human liver, we found that inflammatory conditions preferentially activated the alternative versus proximal PPARGC1A promoter. Gene expression analysis performed in primary mouse hepatocytes identified many shared and isoform-specific roles for PGC-1α variants during acute inflammation. PGC-1α1 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNFα treatment revealed that PGC-1α4 uniquely influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models showed that PGC-1α4 specifically attenuated apoptosis in response to TNFα or LPS, in contrast to PGC-1α1, which reduced expression of a wide inflammatory gene network. We conclude that PGC-1α variants have distinct, yet complimentary roles in hepatic responses to inflammation, with PGC-1α4 being an important mitigator of apoptosis.
2019-06-11 | GSE132458 | GEO
Project description:PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator-1alpha) coactivators regulate adaptive gene expression in response to challenges such as cold exposure, fasting, or physical exercise to balance energy supply and demand. Transcription of a single PGC-1α gene produces different isoforms (e.g. PGC-1α1 to α4) with different biological functions. We aimed to characterize the nuclear interactome for each PGC-1α variant, in particular the transcription factors they bind to regulate gene expression. This was done by generating GST-fusions of all PGC-1a variants, expressed in an insect cell system. These were used to capture associated protein complexes from HeLa nuclear extracts.
2022-03-01 | PXD009232 | Pride
Project description:We investigated gene expression changes in the cardiac tissue of a transgenic mouse model overexpressing Peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform 4 (PGC-1α4) specifically in cardiomyocytes at the neonatal stage and at the age of four weeks.
2022-09-22 | GSE213642 | GEO
Project description:To investigate age-related changes in muscle mitochondrial proteostasis, as well as the effect of higher and lower levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in this paradigm, we isolated RNA from M. gastrocnemius muscle tissue of muscle-specific PGC-1α gain- and loss-of-function mouse models, at the ages of three and twenty four months.
2023-08-04 | GSE233485 | GEO
Project description:The peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) integrates environmental cues by controlling complex transcriptional networks in various metabolically active tissues. However, it is unclear how a transcriptional coregulator coordinates dynamic biological programs in response to multifaceted stimuli such as endurance training or fasting. Here, we discovered a central function of the poorly understood C-terminal domain (CTD) of PGC-1α to bind RNAs and assemble multi-protein complexes. Surprisingly, in addition to controlling the coupling of transcription and processing of target genes, RNA binding is indispensable for the recruitment of PGC-1α to chromatin into liquid-like nuclear condensates, which compartmentalize and regulate active transcription. These results demonstrate a hitherto unsuspected molecular mechanism by which complexity in the regulation of large transcriptional networks by PGC-1α is achieved. These findings are not only essential for the basic understanding of transcriptional coregulator-driven control of biological programs, but will also help to devise new strategies to modulate these processes in pathological contexts in which PGC-1α function is dysregulated, such as type 2 diabetes, cardiovascular diseases or skeletal muscle wasting.
2021-08-19 | PXD026725 | Pride
Project description:The mechanistic underpinnings of the fasting response in skeletal muscle is still poorly understood. We therefore investigated the role of the transcriptional coactivator PGC-1beta (peroxisome proliferator-activated receptor gamma coactivator 1beta) in this context. To do so, the fasting response in quadriceps muscle was assessed in fed and 24 hours fasted mice and compared between wildtype and PGC-1beta muscle-specific knockout mice (both on a C57Bl6/J background). Morphological, functional and transcriptional parameters were determined. The results indicate that PGC-1beta significantly contributes to the metabolic remodelling of skeletal muscle to fasting by promoting catabolic pathways that help to improve energy production and sequester substrates for gluconeogenesis. Accordingly, muscle-specific knockouts for PGC-1beta exhibit mitigated protein degradation and muscle fiber atrophy. These findings contribute to our understanding of muscle plasticity in different metabolic contexts.
2022-11-18 | GSE210904 | GEO
Project description:In the present study we have studied the mechanistic and functional aspects of NCoR1 function in mouse skeletal muscle. NCoR1 muscle-specific knockout mice exhibited an increased oxidative metabolism. Global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC-1alpha) overexpression on oxidative metabolism in skeletal muscle. The repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1alpha-mediated coactivation of ERRalpha. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases. Gene expression of a total of 20 gastrocnemius samples from control (CON, n = 5), NCoR1 muscle-specific knockout (NCoR1 MKO, n = 5), wild type (WT, n = 5) and PGC-1alpha muscle-specific transgenic (PGC-1alpha mTg, n = 5) adult male mice was analyzed using GeneChip® Gene 1.0 ST Array System (Affymetrix). NCoR1 MKO and PGC-1alpha mTg samples were compared to CON and WT samples, respectively.
2013-01-08 | E-GEOD-40439 | biostudies-arrayexpress
Project description:In the present study we have studied the mechanistic and functional aspects of NCoR1 function in mouse skeletal muscle. NCoR1 muscle-specific knockout mice exhibited an increased oxidative metabolism. Global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC-1alpha) overexpression on oxidative metabolism in skeletal muscle. The repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1alpha-mediated coactivation of ERRalpha. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases.
2013-01-08 | GSE40439 | GEO
Project description:Human rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. Although viral induced epithelial damage mediates inflammation, the molecular mechanisms responsible for airway epithelial damage and dysfunction remain undefined. Using experimental HRV infection studies in humans and highly differentiated human bronchial epithelial cells grown at air-liquid interface (ALI), we examined the links between viral host defense, cellular metabolism, and epithelial barrier function. We observed that early HRV-C15 infection induced a transitory barrier-protective metabolic state characterized by glycolysis that ultimately becomes exhausted as the infection progresses and leads to cellular damage. Pharmacological promotion of glycolysis induced ROS-dependent upregulation of the mitochondrial metabolic regulator, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), thereby restoring epithelial barrier function, improving viral defense, and attenuating disease pathology. Therefore, PGC-1alpha regulates a metabolic pathway essential to host defense that can be therapeutically targeted to rescue airway epithelial barrier dysfunction and potentially prevent severe respiratory complications or secondary bacterial infections.
2021-04-30 | PXD024591 | Pride
Project description:Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) transcriptional coactivators are key regulators of energy metabolism-related genes and are expressed in energy-demanding tissues. There are several PGC-1α variants with different biological functions in different tissues. The brain is one of the tissues where the role of PGC-1α isoforms remains less explored. Here, we used a toxin-based mouse model of Parkinson's disease (PD) and observed that the expression levels of variants PGC-1α2 and PGC-1α3 in the nigrostriatal pathway increases at the onset of dopaminergic cell degeneration. This increase occurs concomitant with an increase in glial fibrillary acidic protein levels. Since PGC-1α coactivators regulate cellular adaptive responses, we hypothesized that they could be involved in the modulation of astrogliosis induced by MPTP. Therefore, we analysed the transcriptome of astrocytes transduced with expression vectors encoding PGC-1α1 to 1α4 by massively parallel sequencing (RNA-seq) and identified the main cellular pathways controlled by these isoforms. Interestingly, in reactive astrocytes the inflammatory and antioxidant responses, adhesion, migration, and viability were altered by PGC-1α2 and PGC-1α3, showing that sustained expression of these isoforms induces astrocyte dysfunction and degeneration. This work highlights PGC-1α isoforms as modulators of astrocyte reactivity and potential therapeutic targets for the treatment of PD and other neurodegenerative disorders.
2023-11-27 | GSE248504 | GEO