Abstract
BackgroundMitochondrial 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. However, the role of TFAM in asthma related inflammation remains obscure. The purpose of this study was to investigate the regulatory mechanism of TFAM in asthma.ResultsIn this study, we overexpressed TFAM in human lung epithelial cells (A549), then obtained the TFAM-regulated transcriptome by Illumina sequencing technology. Transcriptome analysis revealed that TFAM overexpression down-regulated and up-regulated the expression of 642 and 169 differentially expressed genes (DEGs), respectively. The TFAM-repressed genes were strongly enriched in cytokine-mediated signaling pathway, type I interferon- and INF-γ-mediated signaling pathways, and viral response pathways. We also revealed that 2563 alternative splicing events in 1796 alternative splicing genes (ASGs) were de-regulated upon TFAM overexpression. These TFAM-responding ASGs were 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 was regulated by TFAM.ConclusionsThese findings suggest that TFAM regulates not only immune response gene expression in human lung epithelial cells, but also pre-mRNA alternative splicing which may mediate transcriptional regulation; this TFAM-centered gene regulation network could be targeted in developing therapies against various diseases.
Highlights
Mitochondrial transcription factor A (TFAM) is associated with a number of neurodegenerative diseases and with asthma
The success of TFAM overexpression was validated by western blot analysis using antibody against the FLAG tag TFAM‐repressed genes are enriched in cytokine‐mediated signaling, interferon response and signaling, viral and immune responses To explore the potential biological functions of the TFAM-regulated genes, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the differentially expressed genes (DEGs)
There were 385 down-regulated and 102 up-regulated DEGs being annotated by GO, and 459 down-regulated and 120 up-regulated DEGs annotated by KEGG (Additional file 6: Table S5)
Summary
Mitochondrial transcription factor A (TFAM) is associated with a number of neurodegenerative diseases and with asthma. TFAM deficiency-induced mitochondrial DNA stress primes the antiviral innate immune response in mouse embryonic fibroblasts. Mitochondrial DNA are emerging as a powerful proinflammatory ligand that can be released into cytosol or extracellular environment to stimulate various pattern-recognition receptors (PRR), such as cGAS, TLR9 and NLRP3 inflammasome, in the innate immune system [2,3,4]. Both cytosolic and extracellular mitochondrial DNA (mtDNA) engage PRRs and trigger type I interferon (IFN) and interferon-stimulated gene (ISG) expression [5]. After exposure to NLRP3 activators, CMPK2-dependent mtDNA synthesis is required for producing cytosolic oxidized mtDNA fragments that associates with the NLRP3 inflammasome complex for the activation of NLRP3 inflammasome in macrophage [6]
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