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Transcriptome analysis of long non-coding RNAs in Mycobacterium avium complex-infected macrophages

ABSTRACT: Mycobacterium avium complex (MAC) is a non-tuberculosis mycobacteria widely distributed throughout environment. Even though the MAC infection is currently increasing in old women and patients with affected immune system, comprehensive analysis of MAC-infected host cell transcriptome, in particular that of long non-coding RNAs (lncRNAs), has scarcely been reported. Using in vitro cultured primary mouse bone marrow-derived macrophages (BMDMs) and CAGE technology, we analyzed the transcriptional and kinetic landscape of macrophage genes, with focusing on lncRNAs, during MAC infection. MAC-infected macrophages induced immune/inflammatory response genes and other genes as similar as M1 activation, consistent with previous reports, although Nos2 and Arg1 revealed distinct expression profiles from M1 activation. We identified 31 up-regulated and 30 down-regulated lncRNA promoters corresponding to 18 and 27 lncRNAs, respectively. The up-regulated lncRNAs were clustered into two groups, early and late up-regulated groups, which were predicted to associate with the immune activation and the immune response to infection, respectively. Further, the Ingenuity IPA analysis predicted canonical pathways and upstream transcription regulators associated with differentially expressed lncRNAs. Several differentially expressed lncRNAs that have been reported elsewhere revealed various expressional change by M1 or M2 pre-activation and the following MAC infection. Finally, we showed that expressional change of lncRNAs in MAC-infected BMDMs is predominantly mediated by Tlr2, but there may be other weakly sensing mechanism for MAC infection. Taken together, we identified differentially expressed lncRNAs in MAC-infected BMDMs, which revealed diverse features implying their distinct role in MAC infection and macrophage polarization.

ORGANISM(S): Mus musculus

PROVIDER: GSE249460 | GEO | 2024/01/01

REPOSITORIES: GEO

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Project description:Long non-coding RNAs (lncRNAs) are transcripts of more than 200 nucleotides that are not translated into functional proteins. Cellular lncRNAs have been shown to act as regulators by interacting with target nucleic acids or proteins and modulating their activities. We investigated the role of RNA1.2, which is one of four major lncRNAs expressed by human cytomegalovirus (HCMV), by comparing the properties of parental virus in vitro with those of deletion mutants lacking either most of the RNA1.2 gene or only the TATA element of the promoter. In comparison with parental virus, these mutants exhibited no growth defects and minimal differences in viral gene expression in human fibroblasts. In contrast, 76 cellular genes were consistently up- or down-regulated by the mutants at both the RNA and protein levels at 72 hours after infection. Differential expression of the gene most highly upregulated by the mutants (Tumor protein p63-regulated gene 1-like protein; TPRG1L) was confirmed at both levels by RT-PCR and immunoblotting. Consistent with the known ability of TPRG1L to upregulate IL-6 expression via NF-κB stimulation, RNA1.2 mutant-infected fibroblasts were observed to upregulate IL-6 in addition to TPRG1L. Comparable surface expression of TNF receptors and responsiveness to TNF-α in cells infected by the parental and mutant viruses indicated that activation of signaling by TNF-α is not involved in upregulation of IL-6 by the mutants. In contrast, inhibition of NF-κB activity and knockdown of TPRG1L expression reduced the extracellular release of IL-6 by RNA1.2 mutant-infected cells, thus demonstrating that upregulation of TPRG1L activates NF-κB. The levels of CCL2 and CXCL1 transcripts were also increased in RNA1.2 mutant-infected cells, further demonstrating the presence of active NF-κB signalling. These results suggest that RNA1.2 plays a role in manipulating intrinsic NF-B-dependent cytokine and chemokine release during HCMV infection , thereby impacting downstream immune responses.

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Transcriptome analysis of long non-coding RNAs in Mycobacterium avium complex-infected macrophages

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