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Title: Expression analysis of wild-type and Tfam heterozygous knockout (Tfam+/-) murine embryonic fibroblasts (MEFs).      
keywords:
Transcriptome or Gene expression
ID:
PRJNA269040
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. Overall design: 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.
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA269040
authentication:
none
authorization:
none
ID:
pmid:25642965
name:
Mus musculus
ncbiID:
ncbitax:10090
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • T32 AI055403/AI/NIAID NIH HHS/United States

  • P01 ES011163/ES/NIEHS NIH HHS/United States

  • R01 AI081884/AI/NIAID NIH HHS/United States

  • R01 AI054359/AI/NIAID NIH HHS/United States

  • MOP37995/Canadian Institutes of Health Research/Canada

  • F32 DK091042/DK/NIDDK NIH HHS/United States

  • UL1 TR000142/TR/NCATS NIH HHS/United States

  • F31 AG039163/AG/NIA NIH HHS/United States

  • R01 AG047632/AG/NIA NIH HHS/United States

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