HIV Tat controls RNA Polymerase II and the epigenetic landscape to transcriptionally reprogram target immune cells.
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.
Department of Biological Sciences, University of Texas at Dallas, Richardson, United States.|Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States.
Jonathan E
JE
Reeder
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States.
Youn-Tae
YT
Kwak
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States.
Ryan P
RP
McNamara
Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States.
Christian V
CV
Forst
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States.
Iván
http://orcid.org/0000-0002-1409-2351
I
D'Orso
D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006678:HIV / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D012319:RNA Polymerase II / Q000378:metabolism*; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D054322:tat Gene Products, Human Immunodeficiency Virus; D012319:RNA Polymerase II
RNA polymerase II; chromatin; chromosomes; epigenetics; genes; human; transcription; transcription factors