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Project description:The HIV regulatory protein Tat enhances viral transcription but also modifies host gene expression, affecting cell functions like cell cycle and apoptosis. Cohort studies indicate that, despite virological suppression, people with HIV (PWH) are at increased risk of comorbidities linked to chronic inflammation, accelerated immune-aging and cellular senescence, sometimes associated with abnormal genomic methylation patterns. In this study, we analyzed whether Tat influences DNA methylation and subsequently impact the transcriptional signature, contributing to inflammation and accelerated aging. To this aim, Jurkat cells were transfected with full-length Tat (Tat101), Tat’s first exon (Tat72), or an empty vector (TetOFF) and DNA methylation changes were assessed. Differentially expressed genes (DEG) were identified via RNA-seq. Results showed that Tat101 expression resulted in major hyper- and hypomethylations changes at individual CpG sites resulting in a slightly global DNA hypermethylation. Methylation changes at gene promoters and bodies resulted in altered gene expression, specifically regulating gene transcription in 5.1% of DEG in Tat101 expressing cells. In contrast Tat72 had a minimal impact on this epigenetic process. The observed differentially methylated and expressed genes were involved in inflammatory responses, lipid antigen presentation, and apoptosis, and may constitute a key epigenetic mechanism contributing to HIV pathogenesis and chronic inflammation.
2025-02-17 | GSE282526 | GEO
Project description:The HIV regulatory protein Tat enhances viral transcription but also modifies host gene expression, affecting cell functions like cell cycle and apoptosis. Cohort studies indicate that, despite virological suppression, people with HIV (PWH) are at increased risk of comorbidities linked to chronic inflammation, accelerated immune-aging and cellular senescence, sometimes associated with abnormal genomic methylation patterns. In this study, we analyzed whether Tat influences DNA methylation and subsequently impact the transcriptional signature, contributing to inflammation and accelerated aging. To this aim, Jurkat cells were transfected with full-length Tat (Tat101), Tat’s first exon (Tat72), or an empty vector (TetOFF) and DNA methylation changes were assessed. Differentially expressed genes (DEG) were identified via RNA-seq. Results showed that Tat101 expression resulted in major hyper- and hypomethylations changes at individual CpG sites resulting in a slightly global DNA hypermethylation. Methylation changes at gene promoters and bodies resulted in altered gene expression, specifically regulating gene transcription in 5.1% of DEG in Tat101 expressing cells. In contrast Tat72 had a minimal impact on this epigenetic process. The observed differentially methylated and expressed genes were involved in inflammatory responses, lipid antigen presentation, and apoptosis, and may constitute a key epigenetic mechanism contributing to HIV pathogenesis and chronic inflammation.
2025-02-17 | GSE282545 | GEO
Project description:Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape
| PRJNA1189115 | ENA
Project description:Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape.[EPIC]
| PRJNA1189095 | ENA
Project description:Intracellular HIV-1 Tat regulator induces epigenetic changes in the DNA methylation landscape [RNA-seq]
| PRJNA1189119 | ENA
Project description:HIV encodes Tat, a small protein that facilitates viral transcription by binding an RNA structure (trans-activating RNA [TAR]) formed on nascent viral pre-messenger RNAs. Besides this well-characterized mechanism, Tat appears to modulate cellular transcription, but the target genes and molecular mechanisms remain poorly understood. We report here that Tat uses unexpected regulatory mechanisms to reprogram target immune cells to promote viral replication and rewire pathways beneficial for the virus. Tat functions through master transcriptional regulators bound at promoters and enhancers, rather than through cellular 'TAR-like' motifs, to both activate and repress gene sets sharing common functional annotations. Despite the complexity of transcriptional regulatory mechanisms in the cell, Tat precisely controls RNA polymerase II recruitment and pause release to fine-tune the initiation and elongation steps in target genes. We propose that a virus with a limited coding capacity has optimized its genome by evolving a small but 'multitasking' protein to simultaneously control viral and cellular transcription.
| S-EPMC4733046 | biostudies-literature
Project description:Though clinical trials for medical applications of dimethyl sulfoxide (DMSO) reported toxicity in the 1960s, later, the FDA classified DMSO in the safest solvent category. DMSO became widely used in many biomedical fields and biological effects were overlooked. Meanwhile, biomedical science has evolved towards sensitive high-throughput techniques and new research areas, including epigenomics and microRNAs. Considering its wide use, especially for cryopreservation and in vitro assays, we evaluated biological effect of DMSO using these technological innovations. We exposed 3D cardiac and hepatic microtissues to medium with or without 0.1% DMSO and analyzed the transcriptome, proteome and DNA methylation profiles. In both tissue types, transcriptome analysis detected >2000 differentially expressed genes affecting similar biological processes, thereby indicating consistent cross-organ actions of DMSO. Furthermore, microRNA analysis revealed large-scale deregulations of cardiac microRNAs and smaller, though still massive, effects in hepatic microtissues. Genome-wide methylation patterns also revealed tissue-specificity. While hepatic microtissues demonstrated non-significant changes, findings from cardiac microtissues suggested disruption of DNA methylation mechanisms leading to genome-wide changes. The extreme changes in microRNAs and alterations in the epigenetic landscape indicate that DMSO is not inert. Its use should be reconsidered, especially for cryopreservation of embryos and oocytes, since it may impact embryonic development.
| S-EPMC6420634 | biostudies-literature
Project description:The present study demonstrates HIV-1 Tat-mediated epigenetic downregulation of microglial miR-124 and its association with microglial activation. Exposure of mouse primary microglia isolated from newborn pups of either sex to HIV-1 Tat resulted in decreased expression of primary miR-124-1, primary miR-124-2 as well as the mature miR-124. In parallel, HIV-1 Tat exposure to mouse primary microglial cells resulted in increased expression of DNA methylation enzymes, such as DNMT1, DNMT3A, and DNMT3B, which were also accompanied by increased global DNA methylation. Bisulfite-converted genomic DNA sequencing in the HIV-1 Tat-exposed mouse primary microglial cells further confirmed increased DNA methylation of the primary miR-124-1 and primary miR-124-2 promoters. Bioinformatic analyses identified MECP2 as a novel 3'-UTR target of miR-124. This was further validated in mouse primary microglial cells wherein HIV-1 Tat-mediated downregulation of miR-124 resulted in increased expression of MECP2, leading in turn to further repression of miR-124 via the feedback loop. In addition to MECP2, miR-124 also modulated the levels of STAT3 through its binding to the 3'-UTR, leading to microglial activation. Luciferase assays and Ago2 immunoprecipitation determined the direct binding between miR-124 and 3'-UTR of both MECP2 and STAT3. Gene silencing of MECP2 and DNMT1 and overexpression of miR-124 blocked HIV-1 Tat-mediated downregulation of miR-124 and microglial activation. In vitro findings were also confirmed in the basal ganglia of SIV-infected rhesus macaques (both sexes). In summary, our findings demonstrate a novel mechanism of HIV-1 Tat-mediated activation of microglia via downregulation of miR-124, leading ultimately to increased MECP2 and STAT3 signaling.SIGNIFICANCE STATEMENT Despite the effectiveness of combination antiretroviral therapy in controlling viremia, the CNS continues to harbor viral reservoirs. The persistence of low-level virus replication leads to the accumulation of early viral proteins, including HIV-1 Tat protein. Understanding the epigenetic/molecular mechanism(s) by which viral proteins, such as HIV-1 Tat, can activate microglia is thus of paramount importance. This study demonstrated that HIV-1 Tat-mediated DNA methylation of the miR-124 promoter leads to its downregulation with a concomitant upregulation of the MECP2-STAT3-IL6, resulting in microglial activation. These findings reveal an unexplored epigenetic/molecular mechanism(s) underlying HIV-1 Tat-mediated microglial activation, thereby providing a potential target for the development of therapeutics aimed at ameliorating microglial activation and neuroinflammation in the context of HIV-1 infection.
| S-EPMC5990983 | biostudies-literature
Project description:HIV-1 induces changes in the miRNA expression profile of infected CD4+ T cells that could improve viral replication. HIV-1 regulator Tat modifies the cellular gene expression and has been appointed as an RNA silencing suppressor. Tat is a 101-residue protein codified by two exons that regulates the elongation of viral transcripts. The first exon of Tat (amino acids 1-72) forms the transcriptionally active protein Tat72, but the presence of the second exon (amino acids 73-101) results in a more competent regulatory protein (Tat101) with additional functions. Intracellular, full-length Tat101 induces functional and morphological changes in CD4+ T cells that contribute to HIV-1 pathogenesis such as delay in T-cell proliferation and protection against FasL-mediated apoptosis. But the precise mechanism by which Tat produces these changes remains unknown. We analyzed how the stable expression of intracellular Tat101 and Tat72 modified the miRNA expression profile in Jurkat cells and if this correlated with changes in apoptotic pathways and cell cycle observed in Tat-expressing cells. Specifically, the enhanced expression of hsa-miR-21 and hsa-miR-222 in Jurkat-Tat101 cells was associated with the reduced expression of target mRNAs encoding proteins related to apoptosis and cell cycle such as PTEN, PDCD4 and CDKN1B. We developed Jurkat cells with stable expression of hsa-miR-21 or hsa-miR-222 and observed a similar pattern to Jurkat-Tat101 in resistance to FasL-mediated apoptosis, cell cycle arrest in G2/M and altered cell morphology. Consequently, upregulation of hsa-miR-21 and hsa-miR-222 by Tat may contribute to protect against apoptosis and to anergy observed in HIV-infected CD4+ T cells.
| S-EPMC5624617 | biostudies-literature
Project description:This study addresses the individual and combined effects of HIV-1 and methamphetamine (N-methyl-1-phenylpropan-2-amine, METH) on cardiac dysfunction in a transgenic mouse model of HIV/AIDS. METH is abused epidemically and is frequently associated with acquisition of HIV-1 infection or AIDS. We employed microarrays to identify mRNA differences in cardiac left ventricle (LV) gene expression following METH administration (10d, 3mg/kg/d, subcutaneously) in C57Bl/6 wild-type littermates (WT) and Tat-expressing transgenic (TG) mice. Arrays identified 880 differentially expressed genes (expression fold change>1.5, p<0.05) following METH exposure, Tat expression, or both. Using pathway enrichment analysis, mRNAs encoding polypeptides for calcium signaling and contractility were altered in the LV samples. Correlative DNA methylation analysis revealed significant LV DNA methylation changes following METH exposure and Tat expression. By combining these data sets, 38 gene promoters (27 related to METH, 11 related to Tat) exhibited differences by both methods of analysis. Among those, only the promoter for CACNA1C that encodes L-type calcium channel Cav1.2 displayed DNA methylation changes concordant with its gene expression change. Quantitative PCR verified that Cav1.2 LV mRNA abundance doubled following METH. Correlative immunoblots specific for Cav1.2 revealed a 3.5-fold increase in protein abundance in METH LVs. Data implicate Cav1.2 in calcium dysregulation and hypercontractility in the murine LV exposed to METH. They suggest a pathogenetic role for METH exposure to promote LV dysfunction that outweighs Tat-induced effects. This study addresses how HIV-1 and methamphetamine comorbidities affect cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation.
2016-05-23 | GSE64158 | GEO