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Cell Rep. 2018 Jan 16;22(3):585-599. doi: 10.1016/j.celrep.2017.12.080.

NF-κB-Chromatin Interactions Drive Diverse Phenotypes by Modulating Transcriptional Noise.

Author information

1
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA.
2
Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
3
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
4
Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536, USA.
5
Department of Cancer Biology and Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: suzanne_gaudet@dfci.harvard.edu.
6
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA. Electronic address: kathryn.miller-jensen@yale.edu.

Abstract

Noisy gene expression generates diverse phenotypes, but little is known about mechanisms that modulate noise. Combining experiments and modeling, we studied how tumor necrosis factor (TNF) initiates noisy expression of latent HIV via the transcription factor nuclear factor κB (NF-κB) and how the HIV genomic integration site modulates noise to generate divergent (low-versus-high) phenotypes of viral activation. We show that TNF-induced transcriptional noise varies more than mean transcript number and that amplification of this noise explains low-versus-high viral activation. For a given integration site, live-cell imaging shows that NF-κB activation correlates with viral activation, but across integration sites, NF-κB activation cannot account for differences in transcriptional noise and phenotypes. Instead, differences in transcriptional noise are associated with differences in chromatin state and RNA polymerase II regulation. We conclude that, whereas NF-κB regulates transcript abundance in each cell, the chromatin environment modulates noise in the population to support diverse HIV activation in response to TNF.

KEYWORDS:

HIV latency; NF-κB signaling; chromatin; gene expression noise; transcriptional bursting

PMID:
29346759
PMCID:
PMC5812697
DOI:
10.1016/j.celrep.2017.12.080
[Indexed for MEDLINE]
Free PMC Article

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