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J Immunol. 2017 Oct 15;199(8):2652-2667. doi: 10.4049/jimmunol.1602033. Epub 2017 Sep 13.

Integration of Kinase and Calcium Signaling at the Level of Chromatin Underlies Inducible Gene Activation in T Cells.

Author information

1
Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom.
2
Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, United Kingdom.
3
Centre for Stem Cells and Regenerative Medicine, King's College London, London SE1 9RT, United Kingdom.
4
Department of Chemistry, Loughborough University, Loughborough LE11 3TU, United Kingdom.
5
Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9PT, United Kingdom.
6
Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester M13 9PT, United Kingdom; and.
7
Warwick Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom.
8
Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, United Kingdom; pawel.paszek@manchester.ac.uk p.n.cockerill@bham.ac.uk.
9
Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; pawel.paszek@manchester.ac.uk p.n.cockerill@bham.ac.uk.

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.

PMID:
28904128
PMCID:
PMC5632840
DOI:
10.4049/jimmunol.1602033
[Indexed for MEDLINE]
Free PMC Article

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