Similar Datasets
Project description:PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and an RNA recognition motif, however the RNA-processing function(s) were poorly investigated over the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export receptor NXF1. Inducible depletion of PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrate that its RNA/NXF1-binding activity is required for the nuclear export of some canonical mitochondrial-related mRNAs and mitochondrial homeostasis. Genome-wide investigations reveal that the nuclear export function is not strictly linked to promoter-binding, identifying in turn novel regulatory targets of PGC-1α in non-homologous end-joining and nucleocytoplasmic transport. These findings provide new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, aging and neurodegeneration.
| S-EPMC10485026 | biostudies-literature
Project description:PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to 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 the potential RNA-processing function(s) 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 receptor NXF1. Inducible depletion of PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrated that its RNA/NXF1-binding activity is required for the nuclear exportof a subset of mRNAsand mitochondrial homeostasis.Genome-wide investigations revealed that the nuclear export function is not strictly linked to PGC-1α-binding promoters, identifyingin turnnovel mRNA nuclear export targets inmRNA- and age-related pathways.These findingsprovide new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, ageing andneurodegeneration.
2023-07-19 | GSE230428 | GEO
Project description:PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to 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 the potential RNA-processing function(s) 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 receptor NXF1. Inducible depletion of PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrated that its RNA/NXF1-binding activity is required for the nuclear exportof a subset of mRNAsand mitochondrial homeostasis.Genome-wide investigations revealed that the nuclear export function is not strictly linked to PGC-1α-binding promoters, identifyingin turnnovel mRNA nuclear export targets inmRNA- and age-related pathways.These findingsprovide new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, ageing andneurodegeneration.
2023-07-19 | GSE230413 | GEO
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
Project description:The master energy homeostasis regulator PGC-1α exhibits a novel mRNA nuclear export function
| PRJNA961112 | ENA
Project description:The master energy homeostasis regulator PGC-1α exhibits a novel mRNA nuclear export function [ChIP-Seq]
| PRJNA961094 | ENA
Project description:The master energy homeostasis regulator PGC-1α exhibits a novel mRNA nuclear export function [RNA-Seq]
| PRJNA961125 | ENA
Project description:EWS (Ewing sarcoma) encodes an RNA/ssDNA binding protein that is frequently rearranged in a number of different cancers by chromosomal translocations. Physiologically, EWS has diverse and essential roles in various organ development and cellular processes. In this study, we uncovered a new role of EWS in mitochondrial homeostasis and energy metabolism. Loss of EWS leads to a significant decrease in mitochondria abundance and activity, which is caused by a rapid degradation of Peroxisome proliferator-activated receptor γ Coactivator (PGC-1α), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1α via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1α and mitochondrial abundance. We found that expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased in the absence of Ews and depletion of Fbxw7 in Ews-null cells restores PGC-1α expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice. Furthermore, expression of mitochondrial biogenesis, respiration and fatty acid β-oxidation genes is significantly reduced in the liver of Ews-null mice. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1α protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation.
| S-EPMC4434744 | biostudies-literature
Project description:Identification of thioredoxin binding protein-2 (TBP-2), which is currently known as thioredoxin interacting protein (TXNIP), as an important binding partner for thioredoxin (TRX) revealed that an evolutionarily conserved reduction-oxidation (redox) signal complex plays an important role for pathophysiology. Due to the reducing activity of TRX, the TRX/TXNIP signal complex has been shown to be an important regulator for redox-related signal transduction in many types of cells in various species. In addition to its role in redox-dependent regulation, TXNIP has cellular functions that are performed in a redox-independent manner, which largely rely on their scaffolding function as an ancestral ?-Arrestin family. Both the redox-dependent and -independent TXNIP functions serve as regulatory pathways in glucose metabolism. This review highlights the key advances in understanding TXNIP function as a master regulator for whole-body glucose homeostasis. The potential for therapeutic advantages of targeting TXNIP in diabetes and the future direction of the study are also discussed.
| S-EPMC7464905 | biostudies-literature
Project description:Plasticity of cells, tissues, and organs is controlled by the coordinated transcription of biological programs. However, the mechanisms orchestrating such context-specific transcriptional networks mediated by the dynamic interplay of transcription factors and coregulators are poorly understood. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a prototypical master regulator of adaptive transcription in various cell types. We now uncovered a central function of the C-terminal domain of PGC-1α to bind RNAs and assemble multiprotein complexes including proteins that control gene transcription and RNA processing. These interactions are important for PGC-1α recruitment to chromatin in transcriptionally active liquid-like nuclear condensates. Notably, such a compartmentalization of active transcription mediated by liquid-liquid phase separation was observed in mouse and human skeletal muscle, revealing a mechanism by which PGC-1α regulates complex transcriptional networks. These findings provide a broad conceptual framework for context-dependent transcriptional control of phenotypic adaptations in metabolically active tissues.
| S-EPMC8433555 | biostudies-literature