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Gene-expression reversal of lncRNAs and associated mRNAs expression in active vs latent HIV infection.

ABSTRACT: Interplay between lncRNAs and mRNAs is rapidly emerging as a key epigenetic mechanism in controlling various cell functions. HIV can actively infect and/or can persist latently for years by manipulating host epigenetics; however, its molecular essence remains undiscovered in entirety. Here for the first time, we delineate the influence of HIV on global lncRNAs expression in monocytic cells lines. Our analysis revealed the expression modulation of nearly 1060 such lncRNAs which are associated with differentially expressed mRNAs in active and latent infection. This suggests a greater role of lncRNAs in regulating transcriptional and post-transcriptional gene expression during HIV infection. The differentially expressed mRNAs were involved in several different biological pathways where immunological networks were most enriched. Importantly, we discovered that HIV induces expression reversal of more than 150 lncRNAs between its active and latent infection. Also, hundreds of unique lncRNAs were identified in both infection conditions. The pathology specific "gene-expression reversal" and "on-and-off" switching of lncRNAs and associated mRNAs may lead to establish the relationship between active and HIV infection.

SUBMITTER: Nair M

PROVIDER: S-EPMC5069461 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Gene-expression reversal of lncRNAs and associated mRNAs expression in active vs latent HIV infection.

Nair Madhavan M Sagar Vidya V Pilakka-Kanthikeel Sudheesh S

Scientific reports 20161019

Interplay between lncRNAs and mRNAs is rapidly emerging as a key epigenetic mechanism in controlling various cell functions. HIV can actively infect and/or can persist latently for years by manipulating host epigenetics; however, its molecular essence remains undiscovered in entirety. Here for the first time, we delineate the influence of HIV on global lncRNAs expression in monocytic cells lines. Our analysis revealed the expression modulation of nearly 1060 such lncRNAs which are associated wit ...[more]

PMID: 27756902

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Project description:Messenger RNA (mRNA) and long noncoding RNA (lncRNA) are two main subgroups of RNAs participating in transcription regulation. With the development of next generation sequencing, increasing lncRNAs are identified. Many hidden functions of lncRNAs are also revealed. However, the differences in lncRNAs and mRNAs are still unclear. For example, we need to determine whether lncRNAs have stronger tissue specificity than mRNAs and which tissues have more lncRNAs expressed. To investigate such tissue expression difference between mRNAs and lncRNAs, we encoded 9339 lncRNAs and 14,294 mRNAs with 71 expression features, including 69 maximum expression features for 69 types of cells, one feature for the maximum expression in all cells, and one expression specificity feature that was measured as Chao-Shen-corrected Shannon's entropy. With advanced feature selection methods, such as maximum relevance minimum redundancy, incremental feature selection methods, and random forest algorithm, 13 features presented the dissimilarity of lncRNAs and mRNAs. The 11 cell subtype features indicated which cell types of the lncRNAs and mRNAs had the largest expression difference. Such cell subtypes may be the potential cell models for lncRNA identification and function investigation. The expression specificity feature suggested that the cell types to express mRNAs and lncRNAs were different. The maximum expression feature suggested that the maximum expression levels of mRNAs and lncRNAs were different. In addition, the rule learning algorithm, repeated incremental pruning to produce error reduction algorithm, was also employed to produce effective classification rules for classifying lncRNAs and mRNAs, which gave competitive results compared with random forest and could give a clearer picture of different expression patterns between lncRNAs and mRNAs. Results not only revealed the heterogeneous expression pattern of lncRNA and mRNA, but also gave rise to the development of a new tool to identify the potential biological functions of such RNA subgroups.

Project description:Non-coding RNAs (ncRNAs) have been previously reported to serve an important role in transcription. In addition, several studies have revealed that long ncRNAs (lncRNAs) have a crucial role in human diseases. However, the association between lncRNAs and inflammation‑induced intestinal macrophages in the intestinal mucosal barrier has remained elusive. In the present study, intestinal macrophages from healthy Sprague Dawley rats were divided into two groups: The experimental group, consisting of intestinal macrophages treated with 1 mg/l lipopolysaccharide (LPS) and the control group, composed of untreated cells. Differentially expressed (DE) lncRNAs and mRNAs between the control and experimental groups were identified using microarray profiling. The levels of DE mRNAs and lncRNAs were measured by reverse transcription‑quantitative PCR (RT‑qPCR). Furthermore, Gene Ontology (GO) and pathway enrichment analyses of DE mRNAs and lncRNAs were performed. To identify core regulatory factors among DE lncRNAs and mRNAs, a lncRNA‑mRNA network was constructed. A total of 357 DE lncRNAs and 542 DE mRNAs between the LPS‑treated and untreated groups were identified (fold-change >1.5; P<0.05). In addition, selected microarray data were confirmed by RT‑qPCR. GO analysis of the DE mRNAs indicated that the biological functions of the upregulated mRNAs included inflammatory response, immune response, metabolic process and signal transduction, whereas those of the downregulated mRNAs were metabolic process, cell cycle, apoptosis and inflammatory response. In addition, pathway enrichment analysis of the upregulated mRNAs revealed that the most enriched pathways were the NF‑κB signaling pathway, B‑cell receptor signaling pathway and apoptosis, while the downregulated mRNAs were significantly involved in metabolic pathways, the phosphatidylinositol signaling system, cytokine‑cytokine receptor interaction and the Toll‑like receptor signaling pathway. The lncRNA‑mRNA co‑expression network suggested that lncRNAs NONMMUT024673 and NONMMUT062258 may have an important role in LPS‑induced intestinal macrophages. The present study identified the DE profiles between LPS‑ and non‑LPS‑treated intestinal macrophages. These DE lncRNAs and mRNAs may be used as potential targets for attenuating excessive inflammatory response in intestinal mucosal barrier dysfunction.

Project description:BackgroundIn vitro, disulfiram activated HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate drug exposure. We assessed the effect of disulfiram on HIV transcription in a dose-escalation study.MethodsIn this prospective dose-escalation study, to optimise disulfiram exposure we included adults with HIV on suppressive antiretroviral therapy, with plasma HIV RNA of less than 50 copies per mL and a CD4 cell count greater than 350 cells per μL. Participants were allocated sequentially to one of three dosing groups (500 mg, 1000 mg, and 2000 mg) and received disulfiram daily for 3 days. Only the staff who did laboratory assays were masked to group assignment. The primary endpoint was change in cell-associated unspliced HIV RNA in CD4 cells. The primary analysis method was a negative binomial regression, with the number of copies as the outcome variable and the input total RNA or plasma volume as an exposure variable, which is equivalent to modelling copies or input. We used these models to estimate changes from before disulfiram to timepoints during and after disulfiram administration. This study is registered with ClinicalTrials.gov, number NCT01944371.FindingsOf 34 participants screened for eligibility at The Alfred Hospital (Melbourne, VIC, Australia), and San Francisco General Hospital (San Francisco, CA, USA), 30 people were enrolled between Sept 24, 2013, and March 31, 2014. The estimated fold increases in cell-associated unspliced HIV RNA from baseline were 1·7 (95% CI 1·3-2·2; p<0·0001) to the timepoint during disulfiram treatment and 2·1 (1·5-2·9; p<0·0001) to the timepoint after disulfiram in the 500 mg group; 1·9 (1·6-2·4; p<0·0001) and 2·5 (1·9-3·3; p<0·0001) in the 1000 mg group; and 1·6 (1·2-2·1; p=0·0026) and 2·1 (1·5-3·1; p=0·0001) in the 2000 mg group. No deaths occurred, and no serious adverse events were noted. Disulfiram was well tolerated at all doses.InterpretationShort-term administration of disulfiram resulted in increases in cell-associated unspliced HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV.FundingThe Foundation for AIDS Research (amfAR); National Institute of Allergy and Infectious Diseases, National Institutes of Health; Australian National Health and Medical Research Council.

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Gene-expression reversal of lncRNAs and associated mRNAs expression in active vs latent HIV infection.

Publications

Gene-expression reversal of lncRNAs and associated mRNAs expression in active vs latent HIV infection.

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