Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human immunodeficiency virus type 1 (HIV-1) Tat protein recruits positive transcription elongation factor b (P-TEFb) to the transactivation response (TAR) RNA structure to facilitate formation of processive transcription elongation complexes (TECs). Here we examine the role of the Tat/TAR-specified cyclin-dependent kinase 9 (CDK9) kinase activity in regulation of HIV-1 transcription elongation and histone methylation. In HIV-1 TECs, P-TEFb phosphorylates the RNA polymerase II (RNAP II) carboxyl-terminal domain (CTD) and the transcription elongation factors SPT5 and Tat-SF1 in a Tat/TAR-dependent manner. Using in vivo chromatin immunoprecipitation analysis, we demonstrate the following distinct properties of the HIV-1 transcription complexes. First, the RNAP II CTD is phosphorylated at Ser 2 and Ser 5 near the promoter and at downstream coding regions. Second, the stable association of SPT5 with the TECs is dependent upon P-TEFb kinase activity. Third, P-TEFb kinase activity is critical for the induction of methylation of histone H3 at lysine 4 and lysine 36 on HIV-1 genes. Flavopiridol, a potent P-TEFb kinase inhibitor, inhibits CTD phosphorylation, stable SPT5 binding, and histone methylation, suggesting that its potent antiviral activity is due to its ability to inhibit several critical and unique steps in HIV-1 transcription elongation.
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PMID:Coordination of transcription factor phosphorylation and histone methylation by the P-TEFb kinase during human immunodeficiency virus type 1 transcription. 1556 63

The human immunodeficiency virus type-1 (HIV-1) infects microglia, macrophages, and astrocytes in the central nervous system (CNS) and may cause severe neurological diseases, such as AIDS-related dementias or progressive encephalopathies, as a result of CNS inflammation and neurotrophin signaling defects associated with expression of viral antigens and HIV-1 replication in the brain. The HIV Tat protein can be endocytosed by surrounding uninfected cells; interacts with transcriptional coactivators/acetyltransferases, p300/CREB-binding protein, and p300/CREB-binding protein-associated factor (PCAF); and induces neuronal apoptosis. Since nerve growth factor (NGF) receptor and brain-derived neurotrophic factor receptor signaling through CREB requires p300 and PCAF histone acetyltransferases, we sought to determine whether HIV-1 Tat coactivator interactions interfere with neurotrophin receptor signaling in neuronal cells. Here, we demonstrate that Tat-coactivator interactions inhibit NGF- and brain-derived neurotrophic factor-responsive CRE trans-activation and neurotrophin protection against apoptosis in PC12 and IMR-32 neuroblastoma cells. Purified recombinant Tat or Tat-derived synthetic peptides, spanning p300- and PCAF-binding sequences, inhibit histone H3/H4 acetylation in vitro. A Tat mutant, TatK28A/K50A, defective for binding p300 and PCAF, neither repressed NGF-responsive CRE transactivation nor inhibited histone acetylation. HIV-1 Tat interacts in PCAF complexes in post-mortem CNS tissues from donor neuro-AIDS patients, as determined by fluorescence resonance energy transfer immunoconfocal microscopy. Importantly, these findings suggest that HIV-1 Tat-coactivator interactions may contribute to neurotrophin signaling impairments and neuronal apoptosis associated with HIV-1 infections of the CNS.
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PMID:HIV-1 Tat interactions with p300 and PCAF transcriptional coactivators inhibit histone acetylation and neurotrophin signaling through CREB. 1561 Oct 41

Barrier to autointegration factor (BAF) is an essential conserved double-stranded DNA-binding protein in metazoans. BAF binds directly to LEM domain nuclear proteins (e.g. LAP2, Emerin, and MAN1), lamin A, homeodomain transcription factors, and human immunodeficiency virus type 1-encoded proteins. BAF influences higher order chromatin structure and is required to assemble nuclei. BAF also facilitates retroviral preintegration complex insertion into target DNA in vitro, through unknown mechanisms. We report that BAF binds directly and selectively to linker histone H1.1 (among three subtypes tested) and core histone H3 with affinities of approximately 700 nm and approximately 100-200 nm, respectively, in vitro and in vivo. Mutations at the bottom and top surfaces of the BAF dimer disrupted or enhanced, respectively, this binding and affected H1 and H3 similarly. Biochemical studies showed that C-terminal residues 108-215 of histone H1.1 and the N-terminal tail plus helix alphaN in the core of histone H3.1 were each necessary and sufficient to bind BAF. Based on its interactions with histones and DNA, we propose BAF might bind nucleosomes in vivo.
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PMID:Binding of barrier to autointegration factor (BAF) to histone H3 and selected linker histones including H1.1. 1620 25

Elucidation of the mechanism of transcriptional silencing of human immunodeficiency virus type 1 (HIV-1) provirus in latently infected cells is crucial to understand the pathophysiology of HIV-1 infection and to develop novel therapies. Here we demonstrate that AP-4 is responsible for the transcriptional repression of HIV-1. We found that AP-4 site within the viral long terminal repeat (LTR) is well conserved in the majority of HIV-1 subtypes and that AP-4 represses HIV-1 gene expression by recruiting histone deacetylase (HDAC) 1 as well as by masking TATA-binding protein to TATA box. AP-4-mediated transcriptional repression was inhibited by an HDAC inhibitor, tricostatin A, and could be exerted even at distant locations from the TATA box. In addition, AP-4 interacted with HDAC1 both in vivo and in vitro. Moreover, chromatin immunoprecipitation assays have revealed that AP-4 and HDAC1 are present in the HIV-1 LTR promoter in latently infected ACH2 and U1 cells, and they are dissociated from the promoter concomitantly with the association of acetylated histone H3, TBP, and RNA polymerase II upon TNF-alpha stimulation of HIV-1 replication. Furthermore, when AP-4 is knocked down by siRNA, HIV-1 production was greatly augmented in cells transfected with a full-length HIV-1 clone. These results suggest that AP-4 may be responsible for transcriptional quiescence of latent HIV-1 provirus and give a molecular basis to the reported efficacy of combination therapy of conventional anti-HIV drugs with an HDAC inhibitor in accelerating the clearance of HIV-1 from individuals infected with the virus.
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PMID:Transcriptional repression of human immunodeficiency virus type 1 by AP-4. 1654 Apr 71

Argonaute proteins are the core components of effector complexes that facilitate RNA interference (RNAi). Small interfering RNAs (siRNAs) targeted to promoter regions mediate transcriptional gene silencing (TGS) in human cells through heterochromatin formation. RNAi effector complexes have yet to be implicated in the mechanism of mammalian TGS. Here we describe the role of the human Argonaute-1 homolog (AGO1) in directing TGS at the promoters for human immunodeficiency virus-1 coreceptor CCR5 and tumor suppressor RASSF1A. AGO1 associates with RNA polymerase II (RNAPII) and is required for histone H3 Lys9 dimethylation and TGS. AGO1, TAR RNA-binding protein-2 (7TRBP2) and Polycomb protein EZH2 colocalize to the siRNA-targeted RASSF1A promoter, implicating Polycomb silencing in the mechanism of mammalian TGS. These results establish a connection between RNAi components AGO1 and TRBP2, RNAPII transcription and Polycomb-regulated control of gene expression.
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PMID:Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells. 1693 26

Sustained silencing of potentially autotoxic acute proinflammatory genes like tumor necrosis factor alpha (TNFalpha) occurs in circulating leukocytes following the early phase of severe systemic inflammation. Aspects of this gene reprogramming suggest the involvement of epigenetic processes. We used THP-1 human promonocytes, which mimic gene silencing when rendered endotoxin-tolerant in vitro, to test whether TNFalpha proximal promoter nucleosomes and transcription factors adapt to an activation-specific profile by developing characteristic chromatin-based silencing marks. We found increased TNFalpha mRNA levels in endotoxin-responsive cells that was preceded by dissociation of heterochromatin-binding protein 1alpha, demethylation of nucleosomal histone H3 lysine 9 (H3(Lys(9))), increased phosphorylation of the adjacent serine 10 (H3(Ser(10))), and recruitment of NF-kappaB RelA/p65 to the TNFalpha promoter. In contrast, endotoxin-tolerant cells repressed production of TNFalpha mRNA, retained binding of heterochromatin-binding protein 1alpha, sustained methylation of H3(Lys(9)), reduced phosphorylation of H3(Ser(10)), and showed diminished binding of NF-kappaB RelA/p65 to the TNFalpha promoter. Similar levels of NF-kappaB p50 occurred at the TNFalpha promoter in the basal state, during active transcription, and in the silenced phenotype. RelB, which acts as a repressor of TNFalpha transcription, remained bound to the promoter during silencing. These results support an immunodeficiency paradigm where epigenetic changes at the promoter of acute proinflammatory genes mediate their repression during the late phase of severe systemic inflammation.
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PMID:Epigenetic silencing of tumor necrosis factor alpha during endotoxin tolerance. 1764 59

Nuclear processes such as transcription, DNA replication and recombination are dynamically regulated by chromatin structure. Eukaryotic transcription is known to be regulated by chromatin-associated proteins containing conserved protein domains that specifically recognize distinct covalent post-translational modifications on histones. However, it has been unclear whether similar mechanisms are involved in mammalian DNA recombination. Here we show that RAG2--an essential component of the RAG1/2 V(D)J recombinase, which mediates antigen-receptor gene assembly--contains a plant homeodomain (PHD) finger that specifically recognizes histone H3 trimethylated at lysine 4 (H3K4me3). The high-resolution crystal structure of the mouse RAG2 PHD finger bound to H3K4me3 reveals the molecular basis of H3K4me3-recognition by RAG2. Mutations that abrogate RAG2's recognition of H3K4me3 severely impair V(D)J recombination in vivo. Reducing the level of H3K4me3 similarly leads to a decrease in V(D)J recombination in vivo. Notably, a conserved tryptophan residue (W453) that constitutes a key structural component of the K4me3-binding surface and is essential for RAG2's recognition of H3K4me3 is mutated in patients with immunodeficiency syndromes. Together, our results identify a new function for histone methylation in mammalian DNA recombination. Furthermore, our results provide the first evidence indicating that disrupting the read-out of histone modifications can cause an inherited human disease.
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PMID:RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. 1803 47

The human immunodeficiency virus (HIV) transactivating Tat protein is not only critical for viral replication but also affects the host immune system by inducing the production of cytokines such as IL-10. This anti-inflammatory cytokine is upregulated during the course of HIV infection, representing an important pathway by which HIV may induce immunodeficiency. Here, we show that, by acting at the membrane, Tat induces IL-10 expression in primary monocytes and promonocytic U937 cells by NF-kappaB-dependent pathways. The trans-dominant negative mutants of NF-kappaB-inducing kinase (NIK), IKKalpha and IKKbeta expressed in our transactivation model, in accordance with the nuclear binding of p65 and p52 NF-kappaB subunits to the IL-10 promoter, suggest the involvement of both classical and alternative NF-kappaB pathways. In inactivated cells, IKKalpha is localized predominantly in the cytoplasm. Interestingly, Tat stimulates IKKalpha translocation from the cytoplasm to the nucleus in monocytes. Chromatin immunoprecipitation (ChIP) assay experiments, after Tat treatment, revealed IKKalpha and CBP/p300 recruitment to the IL-10 promoter and histone H3 phosphorylation (Ser 10) and acetylation (Lys 14) in this region, presumably leading to chromatin remodeling. We demonstrate that, upstream of NF-kappaB, PKC, ERK1/2 and p38 MAP kinases are involved in Tat-induced IKKalpha nuclear translocation and histone H3 modifications on the IL-10 promoter in accordance with the role of these three kinases in IL-10 production. As a whole, the study demonstrates that Tat activates at least three signaling pathways concurrently, including the classical, alternative and IKKalpha pathways, to promote production of IL-10.
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PMID:HIV-1 Tat protein induces IL-10 production in monocytes by classical and alternative NF-kappaB pathways. 1876 Aug 61

The molecular mechanisms utilized by human immunodeficiency virus (HIV) to enter latency are poorly understood. Following the infection of Jurkat T cells with lentiviral vectors that express Tat in cis, gene expression is progressively silenced. Silencing is greatly enhanced when the lentiviral vectors carry an attenuated Tat gene with the H13L mutation. Individual clones of lentivirus-infected cells showed a wide range of shutdown rates, with the majority showing a 50% silencing frequency between 30 to 80 days. The silenced clones characteristically contained a small fraction (0 to 15%) of activated cells that continued to express d2EGFP. When d2EGFP(+) and d2EGFP(-) cell populations were isolated from the shutdown clones, they quickly reverted to the original distribution of inactive and active cells, suggesting that the d2EGFP(+) cells arise from stochastic fluctuations in gene expression. The detailed analysis of transcription initiation and elongation using chromatin immunoprecipitation (ChIP) assays confirms that Tat levels are restricted in the latently infected cells but gradually rise during proviral reactivation. ChIP assays using clones of latently infected cells demonstrate that the latent proviruses carry high levels of deacetylated histones and trimethylated histones. In contrast, the cellular genes IkappaB alpha and GAPDH had high levels of acetylated histones and no trimethylated histones. The levels of trimethylated histone H3 and HP1-alpha associated with HIV proviruses fell rapidly after tumor necrosis factor alpha activation. The progressive shutdown of HIV transcription following infection suggests that epigenetic mechanisms targeting chromatin structures selectively restrict HIV transcription initiation. This decreases Tat production below the levels that are required to sustain HIV gene expression.
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PMID:Epigenetic silencing of human immunodeficiency virus (HIV) transcription by formation of restrictive chromatin structures at the viral long terminal repeat drives the progressive entry of HIV into latency. 1882 56

Protein arginine methyltransferase 6 (PRMT6) is known to catalyze the generation of asymmetric dimethylarginine in polypeptides. Although the cellular role of PRMT6 is not well understood, it has been implicated in human immunodeficiency virus pathogenesis, DNA repair, and transcriptional regulation. PRMT6 is known to methylate histone H3 Arg-2 (H3R2), and this negatively regulates the lysine methylation of H3K4 resulting in gene repression. To identify in a nonbiased manner genes regulated by PRMT6 expression, we performed a microarray analysis on U2OS osteosarcoma cells transfected with control and PRMT6 small interfering RNAs. We identified thrombospondin-1 (TSP-1), a potent natural inhibitor of angiogenesis, as a transcriptional repression target of PRMT6. Moreover, we show that PRMT6-deficient U2OS cells exhibited cell migration defects that were rescued by blocking the secreted TSP-1 with a neutralizing peptide or blocking alpha-TSP-1 antibody. PRMT6 associates with the TSP-1 promoter and regulates the balance of methylation of H3R2 and H3K4, such that in PRMT6-deficient cells H3R2 was hypomethylated and H3K4 was trimethylated at the TSP-1 promoter. Using a TSP-1 promoter reporter gene, we further show that PRMT6 directly regulates the TSP-1 promoter activity. These findings show that TSP-1 is a transcriptional repression target of PRMT6 and suggest that neutralizing the activity of PRMT6 could inhibit tumor progression and therefore may be of cancer therapeutic significance.
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PMID:Thrombospondin-1 is a transcriptional repression target of PRMT6. 1950 93


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