Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+T cells through p65 and H2B phosphorylation

Jasmine Li, Kristine Hardy, Chan Phetsouphanh, Wen Juan Tu, Elissa L Sutcliffe, Robert McCuaig, Christopher R. Sutton, Anjum Zafar, Cynthia Mee Ling Munier, John Zaunders, Yin Xu, Angelo Theodoratos, Abel Tan, Pek SiewLim, Tobias Knaute, Antonia Masch, Johannes Zerweck, Vedran Brezar, Peter J. Milburn, Jenny Dunn & 5 others Marco G Casarotto, Stephen J. Turner, Nabila Seddiki, Anthony D Kelleher, Sudha Rao

Research output: Contribution to journalArticleResearchpeer-review

Abstract

MemoryTcells are characterizedby their rapid transcriptional programs upon re-stimulation. This transcriptional memory response is facilitated by permissive chromatin, but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wideChIP-sequencing ex vivo human CD4+T cells, here, we show that the signaling enzyme, protein kinase C theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to transcriptional-memory-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4+T cells. Within the nucleus, PKC-θ catalytic activity maintains the Ser536 phosphorylation on the p65 subunit of NF-κB (also known as RelA) and can directly influence chromatin accessibility at transcriptional memory genes by regulating H2B deposition through Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight that chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells.

Original languageEnglish
Pages (from-to)2448-2461
Number of pages14
JournalJournal of Cell Science
Volume129
Issue number12
DOIs
Publication statusPublished - 15 Jun 2016
Externally publishedYes

Keywords

  • Chromatin
  • Memory
  • PKC-θ
  • T-cells
  • Transcription

Cite this

Li, Jasmine ; Hardy, Kristine ; Phetsouphanh, Chan ; Tu, Wen Juan ; Sutcliffe, Elissa L ; McCuaig, Robert ; Sutton, Christopher R. ; Zafar, Anjum ; Mee Ling Munier, Cynthia ; Zaunders, John ; Xu, Yin ; Theodoratos, Angelo ; Tan, Abel ; SiewLim, Pek ; Knaute, Tobias ; Masch, Antonia ; Zerweck, Johannes ; Brezar, Vedran ; Milburn, Peter J. ; Dunn, Jenny ; Casarotto, Marco G ; Turner, Stephen J. ; Seddiki, Nabila ; Kelleher, Anthony D ; Rao, Sudha. / Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+T cells through p65 and H2B phosphorylation. In: Journal of Cell Science. 2016 ; Vol. 129, No. 12. pp. 2448-2461.
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abstract = "MemoryTcells are characterizedby their rapid transcriptional programs upon re-stimulation. This transcriptional memory response is facilitated by permissive chromatin, but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wideChIP-sequencing ex vivo human CD4+T cells, here, we show that the signaling enzyme, protein kinase C theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to transcriptional-memory-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4+T cells. Within the nucleus, PKC-θ catalytic activity maintains the Ser536 phosphorylation on the p65 subunit of NF-κB (also known as RelA) and can directly influence chromatin accessibility at transcriptional memory genes by regulating H2B deposition through Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight that chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells.",
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author = "Jasmine Li and Kristine Hardy and Chan Phetsouphanh and Tu, {Wen Juan} and Sutcliffe, {Elissa L} and Robert McCuaig and Sutton, {Christopher R.} and Anjum Zafar and {Mee Ling Munier}, Cynthia and John Zaunders and Yin Xu and Angelo Theodoratos and Abel Tan and Pek SiewLim and Tobias Knaute and Antonia Masch and Johannes Zerweck and Vedran Brezar and Milburn, {Peter J.} and Jenny Dunn and Casarotto, {Marco G} and Turner, {Stephen J.} and Nabila Seddiki and Kelleher, {Anthony D} and Sudha Rao",
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Li, J, Hardy, K, Phetsouphanh, C, Tu, WJ, Sutcliffe, EL, McCuaig, R, Sutton, CR, Zafar, A, Mee Ling Munier, C, Zaunders, J, Xu, Y, Theodoratos, A, Tan, A, SiewLim, P, Knaute, T, Masch, A, Zerweck, J, Brezar, V, Milburn, PJ, Dunn, J, Casarotto, MG, Turner, SJ, Seddiki, N, Kelleher, AD & Rao, S 2016, 'Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+T cells through p65 and H2B phosphorylation' Journal of Cell Science, vol. 129, no. 12, pp. 2448-2461. https://doi.org/10.1242/jcs.181248

Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+T cells through p65 and H2B phosphorylation. / Li, Jasmine; Hardy, Kristine; Phetsouphanh, Chan; Tu, Wen Juan; Sutcliffe, Elissa L; McCuaig, Robert; Sutton, Christopher R.; Zafar, Anjum; Mee Ling Munier, Cynthia; Zaunders, John; Xu, Yin; Theodoratos, Angelo; Tan, Abel; SiewLim, Pek; Knaute, Tobias; Masch, Antonia; Zerweck, Johannes; Brezar, Vedran; Milburn, Peter J.; Dunn, Jenny; Casarotto, Marco G; Turner, Stephen J.; Seddiki, Nabila; Kelleher, Anthony D; Rao, Sudha.

In: Journal of Cell Science, Vol. 129, No. 12, 15.06.2016, p. 2448-2461.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Li, Jasmine

AU - Hardy, Kristine

AU - Phetsouphanh, Chan

AU - Tu, Wen Juan

AU - Sutcliffe, Elissa L

AU - McCuaig, Robert

AU - Sutton, Christopher R.

AU - Zafar, Anjum

AU - Mee Ling Munier, Cynthia

AU - Zaunders, John

AU - Xu, Yin

AU - Theodoratos, Angelo

AU - Tan, Abel

AU - SiewLim, Pek

AU - Knaute, Tobias

AU - Masch, Antonia

AU - Zerweck, Johannes

AU - Brezar, Vedran

AU - Milburn, Peter J.

AU - Dunn, Jenny

AU - Casarotto, Marco G

AU - Turner, Stephen J.

AU - Seddiki, Nabila

AU - Kelleher, Anthony D

AU - Rao, Sudha

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N2 - MemoryTcells are characterizedby their rapid transcriptional programs upon re-stimulation. This transcriptional memory response is facilitated by permissive chromatin, but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wideChIP-sequencing ex vivo human CD4+T cells, here, we show that the signaling enzyme, protein kinase C theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to transcriptional-memory-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4+T cells. Within the nucleus, PKC-θ catalytic activity maintains the Ser536 phosphorylation on the p65 subunit of NF-κB (also known as RelA) and can directly influence chromatin accessibility at transcriptional memory genes by regulating H2B deposition through Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight that chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells.

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KW - Memory

KW - PKC-θ

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