PGC-1α isoform heterodimerization restricts transcription factor docking and limits metabolic adaptations in skeletal muscle
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA839385 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19270829.fastq.gz | Fastqsanger.gz | |||
| SRR19270830.fastq.gz | Fastqsanger.gz | |||
| SRR19270831.fastq.gz | Fastqsanger.gz | |||
| SRR19270832.fastq.gz | Fastqsanger.gz | |||
| SRR19270833.fastq.gz | Fastqsanger.gz |
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Project description:The PGC-1a gene is expressed as several transcriptional coactivator variants that regulate numerous adaptive processes. These include thermogenesis, hepatic metabolism, neuroprotection, and skeletal muscle adaptation to exercise training. To support such diverse functions, PGC-1 isoform expression and activation are under tight tissue- and context-specific control. Notably, PGC-1 isoforms generated by alternative gene promoter usage, and splicing are highly induced in skeletal muscle upon exercise. Here we show that PGC-12 and 3 are PGC-11 dimerization partners that limit its activity. Skeletal muscle PGC-12 and PGC-13 transgenics have reduced exercise performance and strength, which partially overlaps with PGC-1 loss-of-function. Mechanistically, PGC-11/3 dimerization precludes ERR recruitment and coactivation, so their co-expression in skeletal muscle impairs the innate bioenergetic adaptations characteristic of PGC-11 transgenics and reduces oxidative metabolism gene expression and exercise capacity. Removing this break to PGC-1a1 activity may have therapeutic applications in metabolic diseases and increase responsiveness to training.
2022-05-21 | GSE203299 | GEO
Project description:Transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α play crucial roles in regulating cold-induced thermogenesis in brown adipose tissue (BAT). PGC-1α and NT-PGC-1α are highly induced by cold in BAT and subsequently bind to and coactivate many different transcription factors to regulate expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, respiration and thermogenesis. To identify the complete repertoire of PGC-1α and NT-PGC-1α target genes in BAT, we analyzed genome-wide DNA-binding and gene expression profiles. We find that PGC-1α-/NT-PGC-1α binding broadly associates with cold-mediated transcriptional activation. In addition to their known target genes in mitochondrial biogenesis, fatty acid oxidation, respiration and thermogenesis, PGC-1α and NT-PGC-1α target to a broad spectrum of genes involved in diverse biological pathways including ubiquitin-dependent protein catabolism, ribonucleoprotein complex biosynthesis, phospholipid biosynthesis, angiogenesis, glycogen metabolism, phosphorylation, and autophagy. Our findings expand the number of genes and biological pathways that may be regulated by PGC-1α and NT-PGC-1α and provide further insight into the transcriptional regulatory network in which PGC-1α and NT-PGC-1α coordinate a comprehensive transcriptional response in BAT in response to cold.
2018-05-22 | GSE110055 | GEO
Project description:Transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α play crucial roles in regulating cold-induced thermogenesis in brown adipose tissue (BAT). PGC-1α and NT-PGC-1α are highly induced by cold in BAT and subsequently bind to and coactivate many different transcription factors to regulate expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, respiration and thermogenesis. To identify the complete repertoire of PGC-1α and NT-PGC-1α target genes in BAT, we analyzed genome-wide DNA-binding and gene expression profiles. We find that PGC-1α-/NT-PGC-1α binding broadly associates with cold-mediated transcriptional activation. In addition to their known target genes in mitochondrial biogenesis, fatty acid oxidation, respiration and thermogenesis, PGC-1α and NT-PGC-1α target to a broad spectrum of genes involved in diverse biological pathways including ubiquitin-dependent protein catabolism, ribonucleoprotein complex biosynthesis, phospholipid biosynthesis, angiogenesis, glycogen metabolism, phosphorylation, and autophagy. Our findings expand the number of genes and biological pathways that may be regulated by PGC-1α and NT-PGC-1α and provide further insight into the transcriptional regulatory network in which PGC-1α and NT-PGC-1α coordinate a comprehensive transcriptional response in BAT in response to cold.
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Project description:Endurance exercise promotes adaptive growth and improved function of cardiomyocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are coordinated by the transcriptional protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here, we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise and instead confers heart failure after just six weeks of training. Supporting this, rare genetic variants in the human PPARGC1A gene, which encodes PGC-1α, are associated with risk of heart failure in the UK Biobank. We identify the stress-induced cytokine growth-differentiation factor 15 (GDF15) as a key factor increased in PGC-1α–deficient hearts that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PGC-1α expression is associated with higher GDF15 and with fewer cardiomyocytes. These findings implicate a crucial role for cardiomyocyte PGC-1α in enabling healthy heart adaptation to exercise in part through suppression of GDF15.
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Project description:PGC-1α is a transcriptional coactivator that controls expression of metabolic/energetic genes programming cellular responses to nutrient and environmental adaptations such as fasting, cold or exercise. Unlike most other coactivators, PGC-1α contains protein domains involved in RNA binding and processing such as serine/arginine (SR) and RNA Recognition (RRM) motifs. However, little is known regarding the specific RNAs that bind PGC-1α to possibly control specific metabolic and energetic functions. To address this, we have performed single-end enhanced crosslinking and immunoprecipitation (seCLIP)-based transcriptome-wide analysis to identify specific RNA sequences that bind to PGC-1α. Primary hepatocytes were used to perform seCLIP experiments with glucagon-induced endogenous PGC-1α. RNA sequencing reveals that a large fraction of the RNAs bound to PGC-1α were intronic sequences related to genes involved in transcriptional, signaling or metabolic function linked to glucagon and fasting responses, but were not the canonical direct transcriptional targets of PGC-1α, such as OXPHOS or gluconeogenic genes. Validation of this analysis confirmed that among the top scoring RNA sequences bound to PGC-1α were Sik1, Camk1d, Ppard, Klf15, Gfra1 and Slc25a25. PGC-1α depletion decreased a fraction of mRNA transcript levels of these glucagon-induced genes. Importantly, knock-down of these genes affected glucagon-dependent glucose production, a PGC-1α-regulated metabolic pathway. These studies show that PGC-1α largely binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action.
2020-08-14 | GSE152303 | GEO
Project description:The β-adrenergic receptor signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The β-AR activation highly induces transcriptional coactivator PGC-1α and its splice variant N-terminal (NT)-PGC-1α, promoting the transcription program of mitochondrial biogenesis and thermogenesis. In the present study, we evaluated the role of NT-PGC-1α in brown adipocyte energy metabolism by genome-wide profiling of NT-PGC-1α-responsive genes. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1α are highly enriched in mitochondrial pathways including fatty acid transport and β-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1α in the enhancement of mitochondrial function. Moreover, gene expression profiling of NT-PGC-1α revealed activation of distinct metabolic pathways such as glucose, lipid and nucleotide metabolism and of signaling pathways such as RAR and PPAR-γ/RXRα activation in brown adipocytes. Together, our data strengthen our previous findings that NT-PGC-1α is a key regulator of mitochondrial oxidative metabolism and thermogenesis in brown adipocytes and further suggest that NT-PGC-1α influences a broader spectrum of thermogenic processes to meet cellular needs for adaptive thermogenesis. Two samples from two groups: NT-PGC-1α overexpression and empty vector. There are technical replicates (A and B) for each group. Two RNA samples were pooled for each group.
2015-08-07 | E-GEOD-71774 | biostudies-arrayexpress
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:Glioblastoma, the most frequent primary malignant brain tumor in adults, is characterized by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumor cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. We have previously shown that the peroxisome proliferator–activated receptor γ coactivator (PGC)-1α is a key regulator of cellular respiration, proliferation and invasion in glioblastoma. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose. We employed genetic approaches (PGC-1α stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of adenosine monophosphate kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity towards non-glucose nutrients including galactose, fatty acids and ketone bodies. Moreover, spatially resolved multi-omic analysis integrating transcriptomics and matrix-assisted laser desorption/ionization (MALDI) was used to correlate the gene expression pattern of PGC-1α with local metabolic and genetic architecture in human glioblastoma tissue sections. A nutrient switch from glucose to galactose, ketone bodies or fatty acids triggered an initial activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs towards mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under non-glucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with non-hypoxic tumor niches defining a specific metabolic compartment. Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs which result in upregulation of the enzymatic machinery necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data from human glioblastoma samples confirms the relevance of PGC-1α especially in non-hypoxic tumor regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma.
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Project description:PGC-1α in microglia protects against ischemia-induced brain damage in mice. The data suggest that microglia-specific PGC-1α play a key role in limiting ischemia-induced brain damage and potently participates in regulating microglial function. To further clarify the mechanism of PGC-1α, we conducted chromatin immunoprecipitation-sequencing (ChIP-Seq) analysis to identify the targets of PGC-1α in microglia from mPGC-1α mice at 24 h after ischemic stroke. KEGG pathway analysis of these genes identified the mitophagy signaling pathway as one of the most highly enriched pathways. Finally, we demonstrated that PGC-1α induces mitophagy by regulating ULK1 expression in an ERRα-dependent manner, thereby reducing neuroinflammatory reactions.
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Project description:PGC-1α plays a central role in maintaining the mitochondrial and energy metabolism homeostasis, linking external stimuli to the transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and a putative RNA recognition motif, however potential RNA-processing role(s) have remained elusive for the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export factor NXF1. Inducible depletion of endogenous PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrate that the RNA-binding activity is required for nuclear export of co-activated transcripts and mitochondrial homeostasis. Moreover, a quantitative proteomics approach confirmed PGC-1α-dependent RNA transport and mitochondrial-related functions, identifying also novel mRNA nuclear export targets in age-related telomere maintenance. Discovering a novel function for a major cellular homeostasis regulator provides new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, ageing and neurodegenerative diseases.
2023-09-06 | PXD031189 | Pride