Integration of kinase and calcium signaling at the level of chromatin underlies inducible gene activation in T cells

Ruth Brignall, Pierre Cauchy, Sarah Bevington, Bethany Gorman, Angela O. Pisco, James Bagnall, Christopher Boddington, William Rowe, Hazel England, Kevin Rich, Lorraine Schmidt, Nigel P. Dyer, Mark A. Travis, Sascha Ott, Dean A Jackson, Peter Cockerill, Pawel Paszek

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)
173 Downloads (Pure)

Abstract

TCR signaling pathways cooperate to activate the inducible transcription factors NF-κB, NFAT, and AP-1. In this study, using the calcium ionophore ionomycin and/or PMA on Jurkat T cells, we show that the gene expression program associated with activation of TCR signaling is closely related to specific chromatin landscapes. We find that calcium and kinase signaling cooperate to induce chromatin remodeling at ∼2100 chromatin regions, which demonstrate enriched binding motifs for inducible factors and correlate with target gene expression. We found that these regions typically function as inducible enhancers. Many of these elements contain composite NFAT/AP-1 sites, which typically support cooperative binding, thus further reinforcing the need for cooperation between calcium and kinase signaling in the activation of genes in T cells. In contrast, treatment with PMA or ionomycin alone induces chromatin remodeling at far fewer regions (∼600 and ∼350, respectively), which mostly represent a subset of those induced by costimulation. This suggests that the integration of TCR signaling largely occurs at the level of chromatin, which we propose plays a crucial role in regulating T cell activation.
Original languageEnglish
Pages (from-to)2652-2667
Number of pages16
JournalJournal of Immunology
Volume199
Issue number8
Early online date10 Sep 2017
DOIs
Publication statusPublished - 15 Oct 2017

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