Transactivator of Transcription from HIV Type 1 Subtype E Selectively Inhibits TNF Gene Expression via Interference with Chromatin Remodeling of the TNF Locus

Ranjbar, Shahin; Rajsbaum, Ricardo; Goldfeld, Anne E.

doi:10.4049/jimmunol.176.7.4182

Cited by 23 publications

(42 citation statements)

References 56 publications

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“…1 A and C). This is consistent with previous findings that this region is physically accessible to regulatory proteins (5)(6)(7)(8) and associated with acetylated histones (29). The genomic DNA fragment corresponding to HSS-0.8 is small in the BglII digest (Fig.…”

Section: A Specific Dh Pattern At the Tnf/lt Locus In Primary T Lymphsupporting

confidence: 93%

Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers

Tsytsykova

Rajsbaum

Falvo

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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110

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Here we provide a mechanism for specific, efficient transcription of the TNF gene and, potentially, other genes residing within multigene loci. We identify and characterize highly conserved noncoding elements flanking the TNF gene, which undergo activationdependent intrachromosomal interactions. These elements, hypersensitive site (HSS)؊9 and HSS؉3 (9 kb upstream and 3 kb downstream of the TNF gene, respectively), contain DNase I hypersensitive sites in naive, T helper 1, and T helper 2 primary T cells. Both HSS-9 and HSS؉3 inducibly associate with acetylated histones, indicative of chromatin remodeling, bind the transcription factor nuclear factor of activated T cells (NFAT)p in vitro and in vivo, and function as enhancers of NFAT-dependent transactivation mediated by the TNF promoter. Using the chromosome conformation capture assay, we demonstrate that upon T cell activation intrachromosomal looping occurs in the TNF locus. HSS-9 and HSS؉3 each associate with the TNF promoter and with each other, circularizing the TNF gene and bringing NFAT-containing nucleoprotein complexes into close proximity. TNF gene regulation thus reveals a mode of intrachromosomal interaction that combines a looped gene topology with interactions between enhancers and a gene promoter.chromosome conformation capture assay ͉ chromatin ͉ nuclear factor of activated T cells ͉ transcriptional regulation T NF, a critical cytokine involved in the immune response and inflammation, is secreted by multiple classes of cells, including T cells (1, 2). Transcription of the TNF gene is regulated in a cell type-and stimulus-specific fashion through the recruitment of specific sets of transcription factors and coactivators to an Ϸ200-bp promoter region, forming distinct nucleoprotein complexes known as enhanceosomes (3)(4)(5)(6)(7)(8). For example, in T cells, TNF regulation by antigen receptor engagement or calcium influx depends on nuclear factor of activated T cells (NFAT)p binding to conserved DNA motifs in the promoter (3, 5, 9-11).The TNF gene resides in a locus with the lymphotoxin (LT) ␣ and ␤ genes, their coding regions occupying Ϸ12 kb of genomic DNA on human chromosome 6 and mouse chromosome 17. The TNF and LT-␣ genes are in the same transcriptional orientation; LT-␤ is in the opposite orientation (12-15). The intergenic regions of the TNF/LT locus are generally poorly conserved, but they do contain short, highly conserved noncoding sequences (16). Among these is the TNF promoter itself (12-15, 17), which shows almost complete conservation among primate species (18) and complete conservation in humans in the proximal region critical for transcriptional regulation (19).Long-distance interactions between regulatory elements in their native chromatin context comprise a critical aspect of eukaryotic gene regulation. The presence of widely separated (up to hundreds of kilobases) cis-acting regulatory sequences at native gene loci provided the initial evidence for functional interaction between distal regulatory elements (20). Studies that have i...

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Section: A Specific Dh Pattern At the Tnf/lt Locus In Primary T Lymphsupporting

confidence: 93%

Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers

Tsytsykova

Rajsbaum

Falvo

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

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“…As Tat is necessary for HIV-1 replication and is involved in a number of physiopathological effects, therapeutic approaches targeting Tat could be particularly effective in reducing the serious consequences of HIV-1 infection. Differing rates of disease progression correlate with different HIV-1 subtypes (47,74) and different isotypes of Tat have been shown to induce different effects on T-cell function and viability (17,18,27,62,67). This study further highlights the importance of studying the pathological effects of different subtypes of HIV-1 and their proteins.…”

Section: Discussionmentioning

confidence: 97%

“…Interestingly, regardless of the geographic origin of the virus, subtype-specific variations have arisen. More than 90% of HIV-1 subtype C Tat sequenced to date have a C313S mutation (66), whereas the circulating recombinant form AE (CRF_AE) has acquired the F/Y323W change (67). The alteration in CRF_AE has been shown to result in lower Tat-induced TNF expression from T cells (67).…”

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confidence: 99%

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Human Immunodeficiency Virus Type 1 Subtype C Tat Fails To Induce Intracellular Calcium Flux and Induces Reduced Tumor Necrosis Factor Production from Monocytes

Campbell

Watkins

Singh

et al. 2007

J Virol

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Over 50% of all human immunodeficiency virus type 1 (HIV-1) infections worldwide are caused by subtype C strains, yet most research to date focuses on subtype B, the subtype most commonly found in North America and Europe. The HIV-1 trans-acting regulatory protein (Tat) is essential for regulating productive replication of HIV-1. Tat is secreted by HIV-infected cells and alters several functions of uninfected bystander cells. One such function is that, by acting at the cell membrane, subtype B Tat stimulates the production of tumor necrosis factor (TNF) and chemokine (C-C motif) ligand 2 (CCL2) from human monocytes and can act as a chemoattractant. In this study, we show that the mutation of a cysteine to a serine at residue 31 of Tat commonly found in subtype C variants significantly inhibits the abilities of the protein to bind to chemokine (C-C motif) receptor 2 (CCR2), induce intracellular calcium flux, stimulate TNF and CCL2 production, and inhibit its chemoattractant properties. We also show that TNF is important in mediating some effects of extracellular Tat. This report therefore demonstrates the important functional differences between subtype C and subtype B Tat and highlights the need for further investigation into the different strains of HIV-1.

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“…While a large number of HIV-1 and HIV-2 subtypes contain three copies of Sp1 binding sites in the core promoter, a few simian immunodeficiency virus (SIV) strains contain four copies (9). Likewise, while a large number of HIV-1 subtypes (A, B, D, F, G, H, J, and K) and several subtypes of SIV contain two copies of NF-B binding sites in the enhancer, subtype A/E of HIV-1 (10,11), all HIV-2 subtypes, and the other strains of SIV contain a single NF-B binding site. Subtype C of HIV-1 is the only viral family that contains three binding sites for NF-B (12)(13)(14)(15).…”

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confidence: 99%

Functional Incompatibility between the Generic NF-κB Motif and a Subtype-Specific Sp1III Element Drives the Formation of the HIV-1 Subtype C Viral Promoter

Verma

Rajagopalan

Lotke

et al. 2016

J Virol

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Of the various genetic subtypes of human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and simian immunodeficiency virus (SIV), only in subtype C of HIV-1 is a genetically variant NF-B binding site found at the core of the viral promoter in association with a subtype-specific Sp1III motif. How the subtype-associated variations in the core transcription factor binding sites (TFBS) influence gene expression from the viral promoter has not been examined previously. Using panels of infectious viral molecular clones, we demonstrate that subtype-specific NF-B and Sp1III motifs have evolved for optimal gene expression, and neither of the motifs can be replaced by a corresponding TFBS variant. The variant NF-B motif binds NF-B with an affinity 2-fold higher than that of the generic NF-B site. Importantly, in the context of an infectious virus, the subtype-specific Based on genetic variation, human immunodeficiency virus type 1 (HIV-1) is classified into four distinct groups (M, N, O, and P), and group M is subclassified into nine molecular subtypes (A, B, C, D, F, G, H, J, and K) and numerous circulating recombinant forms, including A/E (1). The global distribution of HIV-1 subtypes is uneven, with C, A, and B being the most widespread subtypes. Subtype C is predominant in southern and eastern African countries, India, and Nepal and in recombinant forms in China, and it is currently emerging in southern Brazil. Subtype C is responsible for approximately half of the global HIV-1 infections and more than 95% of the infections in India (2). The factors that contribute to the widespread expansion of subtype C are not well understood. Diverse viral subtypes differ from one another up to 30 to 35% in certain gene segments, such as the envelope (3). A genetic variation to this large an extent is expected to have a significant impact on the biological properties of the subtypes influencing their relative fitness properties. Subtype-specific genetic variations in elements such as the viral promoter (enhancer and other regulatory elements), regulatory proteins, and structural proteins may underlie the biological differences, although drawing such a correlation between these factors may not always be possible.The individual components of the viral promoter, including the modulator region, the enhancer, and the core promoter, are characterized by several subtype-specific molecular variations. Such differences have been mapped to many transcription factor binding sites (TFBS), including USF, c-Myb, NF-AT, Ap-1, NF-B, and Sp1, and regulatory elements such as the TATA box and

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Transactivator of Transcription from HIV Type 1 Subtype E Selectively Inhibits TNF Gene Expression via Interference with Chromatin Remodeling of the TNF Locus

Cited by 23 publications

References 56 publications

Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers

Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers

Human Immunodeficiency Virus Type 1 Subtype C Tat Fails To Induce Intracellular Calcium Flux and Induces Reduced Tumor Necrosis Factor Production from Monocytes

Functional Incompatibility between the Generic NF-κB Motif and a Subtype-Specific Sp1III Element Drives the Formation of the HIV-1 Subtype C Viral Promoter

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