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

Jonathan E Reeder,Ryan P Mcnamara,Youn-Tae Kwak,Iván D'Orso,Christian V Forst

doi:10.7554/elife.08955

Abstract

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.

Highlights

Transcription of protein coding genes by RNA Polymerase (Pol) II is regulated at several steps including initiation, elongation and termination (Adelman and Lis, 2012; Fuda et al, 2009; Grunberg and Hahn, 2013; Sims et al, 2004; Zhou et al, 2012)
We found that Tat is recruited to both promoters (39%) and intragenic domains (39%) at Tat stimulated genes (TSG), whereas the majority of occupied domains at Tat down-regulated genes (TDG) are at promoters (61%) (Figure 1—figure supplement 5)
Given that we found intragenic enhancers containing a form of Pol II that appears to be paused, and that enhancer–promoter interactions are frequently associated with paused Pol II (GhaviHelm et al, 2014), we speculated that the original TR algorithm might not accurately describe Tat’s role in transcription elongation in our dataset

Summary

Introduction

Transcription of protein coding genes by RNA Polymerase (Pol) II is regulated at several steps including initiation, elongation and termination (Adelman and Lis, 2012; Fuda et al, 2009; Grunberg and Hahn, 2013; Sims et al, 2004; Zhou et al, 2012). While one group of transcription factors recruit Pol II to their target genes to induce transcription initiation, another class functions by promoting the transcriptional pause release from the promoter-proximal state to allow Pol II transition to the productive elongation phase (Feinberg et al, 1991; Gomes et al, 2006; Peterlin and Price, 2006; Rahl et al, 2010; Zhou et al, 2012). The study of chromatin modifications has revealed fundamental concepts in the regulation

Methods

Results

Conclusion