Transcriptional responses in TFAM-deficient renal epithelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE147189 | GEO | 2021/06/28
REPOSITORIES: GEO
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Project description:Transcriptional responses in TFAM-deficient renal epithelial cells
| PRJNA613286 | ENA
Project description:SIRT3 is a NAD+-dependent mitochondrial protein deacetylase participating in the regulation of central metabolism and mitochondrial proteostasis. SIRT3 is downregulated in clear cell renal cell carcinoma (ccRCC), a main type of renal cancers, but the function of SIRT3 in tumorigenesis and development of ccRCC remains unknown. In this study, we established a SIRT3 overexpressed cell line to explore the changes of proteomics and metabolomics regulated by SIRT3 expression. Both the results of quantitative proteomics, metabolomics and acetylome showed overexpression of SIRT3 increased mitochondrial biogenesis and reversed the mitochondrial dysfunctions in ccRCC. We found SIRT3 could increase the activity of TFAM through modulation of TFAM transcription, degradation and acetylation level. The acetylation of TFAM K154 decreased while TFAM protein expression increased after SIRT3 overexpression. Further study revealed that SIRT3 could bind with TFAM, and decrease the acetylation of TFAM, promoting TFAM activity in mitochondrial biogenesis. Overall, our results present a new mechanism of SIRT3 in regulating mitochondrial functions, and the downregulation of SIRT3 in ccRCC lowers the activity of TFAM, subsequently inhibits the transcription of mitochondrial genes and mitochondrial biogenesis.
2018-08-14 | PXD009110 | Pride
Project description:To identify novel transcriptional targets following Qpc inactivation. We deleteted Qpc in SIX2 nephron progenitor cells using a Six2-eGFP/cre BAC transgene. We compared SIX2-expressing progenitors from Six2-Qpc-/- kidneys with control (Six2-Qpc+/-) embryonic kidneys at E18.5.
2022-06-29 | GSE158299 | GEO
Project description:To investigate the role of Egfr in the cerebreal cortex and hippocampal formation we conditionally deleted it using a floxed allele in combination with the Nestin-cre transgene. Cortices at E17.5 embryonic stage were harvested and split into rostral and caudal halves and RNA extracted and sequenced
2022-06-09 | GSE205624 | GEO
Project description:To investigate the role of Egfr in the cerebreal cortex and hippocampal formation we conditionally deleted it using a floxed allele in combination with the Nestin-cre transgene. Cortices at P5 post-natal stage were harvested and split into rostral and caudal halves and RNA extracted and sequenced
2022-10-02 | GSE214424 | GEO
Project description:ChIP-seq data characterizing the occupancy of TFAM over the mitochondrial and nuclear genomes in HeLa cells. Characterization of mitochondrial and nuclear genome-wide TFAM binding in HeLa cells
2013-09-21 | E-GEOD-48176 | biostudies-arrayexpress
Project description:The goal of this analysis was to utilize microarray profiling to identify basal alterations in gene expression in response to TFAM depletion and mtDNA stress. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein, TFAM (transcription factor A,mitochondrial), regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signaling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity. Murine embryonic fibroblasts were isolated from wild-type or Tfam+/- E13.5 littermate embryos. RNA from passage-matched wild-type and Tfam+/- MEF lines was extracted in duplicate and hybridized onto Affymetrix microarrays. Four arrays were performed in total with two technical replicates per genotype.
2015-01-26 | E-GEOD-63767 | biostudies-arrayexpress
Project description:Gene expression analysis of 2-month-old Ctrl and Tfam-SCKO mice. At this age mitochondrial function is disrupted in the Schwann cells of Tfam-SCKO mice ,but their nerves display only very limited pathology. Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells, SCs) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response through actions of heme-regulated inhibitor kinase (HRI), and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines, an intermediate of fatty acid b-oxidation. Importantly, we show that acylcarnitines are released from SCs and induce axonal degeneration. A maladaptive integrated stress response as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies. Total RNA samples were prepared by isolating and pooling RNA from three different 2-month-old MPZ-Tfam KO and Ctrl mice. 2 replicates per genotype were used in this experiment and they were prepared entirely independently.
2013-03-13 | E-GEOD-44605 | biostudies-arrayexpress
Project description:Mitochondrial transcription factor A (TFAM) is associated with a number of neurodegenerative diseases and also with asthma. TFAM deficiency-induced mitochondrial DNA stress primes the antiviral innate immune response in mouse embryonic fibroblasts. In this study, we overexpressed TFAM in human lung epithelial cells (A549), then obtained and analyzed the TFAM-regulated transcriptome by Illumina-sequencing technology. We found that TFAM overexpression down-regulated and up-regulated the expression 642 and 169 genes (DEGs), respectively. The TFAM-repressed genes were highly enriched in cytokine-mediated signaling pathway, type I interferon- and INFmediated signaling pathways, and viral response pathways. We also revealed that 2563 alternative splicing events in 1796 genes (ASG) were de-regulated upon TFAM overexpression. These TFAM-responding ASGs were strongly enriched in DNA repair, nerve growth factor receptor signaling pathway, and also transcription regulation. Further analysis revealed that the promoters of TFAM-repressed DEGs were enriched by DNA binding motifs of transcription factors whose alternative splicing regulated by TFAM. These findings suggested that TFAM regulates not only immune response gene expression in human lung epithelial cells, but also alternative splicing which may play a role in mediating transcriptional regulation. This TFAM-centered gene regulation network could be targeted in developing therapies against various diseases.
2021-12-15 | GSE162384 | GEO
Project description:The major consumers of oxygen in the cell are mitochondria. Here we identified an oxygen-sensitive regulation of TFAM, a key activator of mitochondrial transcription and replication. TFAM is hydroxylated by EglN3 on proline 53/56 and subsequently bound by the tumor suppressor von Hippel Lindau (pVHL). pVHL binding stabilizes TFAM by preventing mitochondrial LON proteolysis. Cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen have reduced mitochondria. All VHL cancer syndrome mutations tested, type 1, 2A, 2B, 2C, failed to bind hydroxylated TFAM, regardless of whether they have the ability to bind hydroxylated HIFa or not. In contrast, VHL-R200W polycythemia-mutation bound hydroxylated TFAM similar as wild-type VHL. VHL-R200W causes polycythemia with total absence of tumor development, despite increased HIFa signaling. Tumors of VHL related malignancies such as pheochromocytoma and renal carcinoma cells show low mitochondrial content, implicating that impaired mitochondrial biogenesis is linked to the malignancies of the VHL hereditary cancer syndrome.
2022-05-25 | PXD022734 | Pride