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An upstream YY1 binding site on the HIV-1 LTR contributes to latent infection.

ABSTRACT: During HIV-1 infection a population of latently infected cells is established. This population is the major obstacle preventing total eradication of the virus from AIDS patients. HIV-1 latency is thought to arise by various mechanisms including repressive chromatin modifications. Transcription factors such as YY1 have been shown to facilitate repressive chromatin modifications by the recruitment of histone deacetylases. In this study, we identified a novel binding site for YY1 on the HIV-1 LTR, 120 nucleotides upstream of the transcription start site. We show that YY1 can bind to this site in vitro and in vivo and that binding to the LTR is dissociated upon T cell activation. Overexpression of YY1 causes an increase in the proportion of cells that produce latent infections. These observations, in combination with previous results, demonstrate that YY1 plays a prominent role in controlling the establishment and maintenance of latent HIV-1 provirus in unstimulated cells.

SUBMITTER: Bernhard W

PROVIDER: S-EPMC3792934 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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An upstream YY1 binding site on the HIV-1 LTR contributes to latent infection.

Bernhard Wendy W Barreto Kris K Raithatha Sheetal S Sadowski Ivan I

PloS one 20131008 10

During HIV-1 infection a population of latently infected cells is established. This population is the major obstacle preventing total eradication of the virus from AIDS patients. HIV-1 latency is thought to arise by various mechanisms including repressive chromatin modifications. Transcription factors such as YY1 have been shown to facilitate repressive chromatin modifications by the recruitment of histone deacetylases. In this study, we identified a novel binding site for YY1 on the HIV-1 LTR, ...[more]

PMID: 24116200

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Project description:Distinct viral gene expression characterizes Epstein-Barr virus (EBV) infection in EBV-producing marmoset B-cell (B95-8) and EBV-associated gastric carcinoma (SNU719) cell lines. CCCTC-binding factor (CTCF) is a structural chromatin factor that coordinates chromatin interactions in the EBV genome. Chromatin immunoprecipitation followed by sequencing against CTCF revealed 16 CTCF binding sites in the B95-8 and SNU719 EBV genomes. The biological function of one CTCF binding site (S13 locus) located on the BamHI A right transcript (BART) miRNA promoter was elucidated experimentally. Microscale thermophoresis assay showed that CTCF binds more readily to the stable form than the mutant form of the S13 locus. EBV BART miRNA clusters encode 22 miRNAs, whose roles are implicated in EBV-related cancer pathogenesis. The B95-8 EBV genome lacks a 11.8-kb EcoRI C fragment, whereas the SNU719 EBV genome is full-length. ChIP-PCR assay revealed that CTCF, RNA polymerase II, H3K4me3 histone, and H3K9me3 histone were more enriched at S13 and S16 (167-kb) loci in B95-8 than in the SNU719 EBV genome. 4C-Seq and 3C-PCR assays using B95-8 and SNU719 cells showed that the S13 locus was associated with overall EBV genomic loci including 3-kb and 167-kb region in both EBV genomes. We generated mutations in the S13 locus in bacmids with or without the 11.8-kb BART transcript unit (BART(+/-)). The S13 mutation upregulated BART miRNA expression, weakened EBV latency, and reduced EBV infectivity in the presence of EcoRI C fragment. Another 3C-PCR assay using four types of BART(+/-)·S13(wild-type(Wt)/mutant(Mt)) HEK293-EBV cells revealed that the S13 mutation decreased DNA associations between the 167-kb region and 3-kb in the EBV genome. Based on these results, CTCF bound to the S13 locus along with the 11.8-kb EcoRI C fragment is suggested to form an EBV 3-dimensional DNA loop for coordinated EBV BART miRNA expression and infectivity. Author summary A CCCTC-binding factor binding site (S13 locus) on the BamHI A right transcript miRNA promoter was identified by Chromatin immunoprecipitation followed by sequencing and MST assays. Next, we investigated the functional roles of the S13 locus using reverse genetics followed by 4C-Seq and 3C-PCR assays. We found that in the presence of the 11.8-kb EcoRI C fragment, the S13 locus is associated with overall EBV genomic loci including 3-kb (S1) and 167-kb (S16). Reverse genetic studies demonstrated that the S13 locus plays an inhibitory role in EBV BART miRNA expression and lytic reactivation in the presence of the EcoRI C fragment. Thus, the S13 locus is suggested to form a cluster of DNA loops with the OriP (S1) and LMP1/2 (S16) loci to coordinate the EBV life cycle.

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An upstream YY1 binding site on the HIV-1 LTR contributes to latent infection.

Publications

An upstream YY1 binding site on the HIV-1 LTR contributes to latent infection.

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