HIV Tat controls RNA Polymerase II and the epigenetic landscape to transcriptionally reprogram target immune cells

  1. Jonathan E Reeder
  2. Youn-Tae Kwak
  3. Ryan P McNamara
  4. Christian V Forst
  5. Iván D'Orso  Is a corresponding author
  1. University of Texas at Dallas, United States
  2. University of Texas Southwestern Medical Center, United States
  3. Icahn School of Medicine at Mount Sinai, United States

Abstract

HIV encodes Tat, a small protein that facilitates viral transcription by binding an RNA structure (TAR) formed on nascent viral pre-mRNAs. 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. We propose that a virus with a limited coding capacity optimized its genome by evolving a small but 'multitasking' protein to simultaneously control viral and cellular transcription.

Article and author information

Author details

  1. Jonathan E Reeder

    Biology, University of Texas at Dallas, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Youn-Tae Kwak

    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ryan P McNamara

    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Christian V Forst

    Department of Genetics and Genomc Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Iván D'Orso

    Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Ivan.Dorso@UTSouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2015, Reeder et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,037
    views
  • 727
    downloads
  • 44
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jonathan E Reeder
  2. Youn-Tae Kwak
  3. Ryan P McNamara
  4. Christian V Forst
  5. Iván D'Orso
(2015)
HIV Tat controls RNA Polymerase II and the epigenetic landscape to transcriptionally reprogram target immune cells
eLife 4:e08955.
https://doi.org/10.7554/eLife.08955

Share this article

https://doi.org/10.7554/eLife.08955

Further reading

    1. Chromosomes and Gene Expression
    2. Microbiology and Infectious Disease
    Maruti Nandan Rai, Qing Lan ... Koon Ho Wong
    Research Article Updated

    Candida glabrata can thrive inside macrophages and tolerate high levels of azole antifungals. These innate abilities render infections by this human pathogen a clinical challenge. How C. glabrata reacts inside macrophages and what is the molecular basis of its drug tolerance are not well understood. Here, we mapped genome-wide RNA polymerase II (RNAPII) occupancy in C. glabrata to delineate its transcriptional responses during macrophage infection in high temporal resolution. RNAPII profiles revealed dynamic C. glabrata responses to macrophages with genes of specialized pathways activated chronologically at different times of infection. We identified an uncharacterized transcription factor (CgXbp1) important for the chronological macrophage response, survival in macrophages, and virulence. Genome-wide mapping of CgXbp1 direct targets further revealed its multi-faceted functions, regulating not only virulence-related genes but also genes associated with drug resistance. Finally, we showed that CgXbp1 indeed also affects fluconazole resistance. Overall, this work presents a powerful approach for examining host-pathogen interaction and uncovers a novel transcription factor important for C. glabrata’s survival in macrophages and drug tolerance.

    1. Chromosomes and Gene Expression
    2. Neuroscience
    Robyn D Moir, Emilio Merheb ... Ian M Willis
    Research Article

    Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of Polr3-related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of Polr3-related disease pathogenesis is unknown. We developed a postnatal whole-body mouse model expressing pathogenic Polr3a mutations to examine the molecular mechanisms by which reduced Pol III transcription results primarily in central nervous system phenotypes. Polr3a mutant mice exhibit behavioral deficits, cerebral pathology and exocrine pancreatic atrophy. Transcriptome and immunohistochemistry analyses of cerebra during disease progression show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell-type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. Earlier in the disease when integrated stress and innate immune responses are minimally induced, mature tRNA sequencing revealed a global reduction in tRNA levels and an altered tRNA profile but no changes in other Pol III transcripts. Thus, changes in the size and/or composition of the tRNA pool have a causal role in disease initiation. Our findings reveal different tissue- and brain region-specific sensitivities to a defect in Pol III transcription.