Imperial College London
Alternate

ProfessorCharlesBangham

Institute of Infection

Co-Director of the Institute of Infection
 
 
 
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Contact

 

+44 (0)20 7594 3730c.bangham Website

 
 
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Assistant

 

Ms Linda Hollick +44 (0)20 7594 3729

 
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Location

 

115Wright Fleming WingSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Bangham:2018:10.1172/jci.insight.123196,
author = {Bangham, CRM and Taylor, GP and Klose, RJ and Schofield, CJ and Kulkarni, A},
doi = {10.1172/jci.insight.123196},
journal = {Journal of Clinical Investigation},
title = {Histone H2A mono-ubiquitylation and p38-MAP Kinases regulate immediate-early gene-like reactivation of latent retrovirus HTLV-1},
url = {http://dx.doi.org/10.1172/jci.insight.123196},
volume = {3},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - It is not understood how the human T cell leukemia virus human T-lymphotropic virus-1 (HTLV-1), a retrovirus, regulates the in vivo balance between transcriptional latency and reactivation. The HTLV-1 proviral plus-strand is typically transcriptionally silent in freshly isolated peripheral blood mononuclear cells from infected individuals, but after short-term ex vivo culture, there is a strong, spontaneous burst of proviral plus-strand transcription. Here, we demonstrate that proviral reactivation in freshly isolated, naturally infected primary CD4+ T cells has 3 key attributes characteristic of an immediate-early gene. Plus-strand transcription is p38-MAPK dependent and is not inhibited by protein synthesis inhibitors. Ubiquitylation of histone H2A (H2AK119ub1), a signature of polycomb repressive complex-1 (PRC1), is enriched at the latent HTLV-1 provirus, and immediate-early proviral reactivation is associated with rapid deubiquitylation of H2A at the provirus. Inhibition of deubiquitylation by the deubiquitinase (DUB) inhibitor PR619 reverses H2AK119ub1 depletion and strongly inhibits plus-strand transcription. We conclude that the HTLV-1 proviral plus-strand is regulated with characteristics of a cellular immediate-early gene, with a PRC1-dependent bivalent promoter sensitive to p38-MAPK signaling. Finally, we compare the epigenetic signatures of p38-MAPK inhibition, DUB inhibition, and glucose deprivation at the HTLV-1 provirus, and we show that these pathways act as independent checkpoints regulating proviral reactivation from latency.
AU  - Bangham,CRM
AU  - Taylor,GP
AU  - Klose,RJ
AU  - Schofield,CJ
AU  - Kulkarni,A
DO  - 10.1172/jci.insight.123196
PY  - 2018///
SN  - 0021-9738
TI  - Histone H2A mono-ubiquitylation and p38-MAP Kinases regulate immediate-early gene-like reactivation of latent retrovirus HTLV-1
T2  - Journal of Clinical Investigation
UR  - http://dx.doi.org/10.1172/jci.insight.123196
UR  - http://hdl.handle.net/10044/1/63983
VL  - 3
ER  -
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