Priming of transcriptional memory responses via the chromatin accessibility landscape in T cells

Wen Juan Tu,Christopher R Sutton,Gareth Denyer,Corey Smith,Vedran Brezar,Stephen J Turner,Melanie Morris,Jenny Dunn,Sau Kuen Lee,Kristine Hardy,Rajiv Khanna,Abel Tan,Robert Mccuaig,Sudha Rao,Nabila Seddiki,Jasmine Li

doi:10.1038/srep44825

Abstract

Memory T cells exhibit transcriptional memory and “remember” their previous pathogenic encounter to increase transcription on re-infection. However, how this transcriptional priming response is regulated is unknown. Here we performed global FAIRE-seq profiling of chromatin accessibility in a human T cell transcriptional memory model. Primary activation induced persistent accessibility changes, and secondary activation induced secondary-specific opening of previously less accessible regions associated with enhanced expression of memory-responsive genes. Increased accessibility occurred largely in distal regulatory regions and was associated with increased histone acetylation and relative H3.3 deposition. The enhanced re-stimulation response was linked to the strength of initial PKC-induced signalling, and PKC-sensitive increases in accessibility upon initial stimulation showed higher accessibility on re-stimulation. While accessibility maintenance was associated with ETS-1, accessibility at re-stimulation-specific regions was linked to NFAT, especially in combination with ETS-1, EGR, GATA, NFκB, and NR4A. Furthermore, NFATC1 was directly regulated by ETS-1 at an enhancer region. In contrast to the factors that increased accessibility, signalling from bHLH and ZEB family members enhanced decreased accessibility upon re-stimulation. Interplay between distal regulatory elements, accessibility, and the combined action of sequence-specific transcription factors allows transcriptional memory-responsive genes to “remember” their initial environmental encounter.

Highlights

Naïve T cells exist at rest until exposed to activating signals from antigen presenting cells
protein kinase C (PKC)-θsignalling activates a number of transcription factors including the NFκB family members as well as AP1 and NFAT8,13,14, which have a major role in regulating chromatin configuration upon T cell activation[15,16]
We used a human T cell culture model with stimuli acting downstream of cell surface signalling to explore if the chromatin accessibility landscape “remembers” previous activation and to identify the transcription factors required to establish and enhance the chromatin accessibility changes associated with rapid gene expression upon re-stimulation

Summary

Introduction

Naïve T cells exist at rest until exposed to activating signals from antigen presenting cells. In contrast to naïve T cells, memory T cells are primed for a rapid response to antigenic re-exposure[1,2,3] This enhanced response is in part attributed to more efficient T cell receptor (TCR) signalling such as increased activity of ZAP-704, the MAP kinases[5,6], and protein kinase C (PKC)[7]. Histone modifications[19] and the incorporation of histone variants[20,21] regulate histone-DNA interactions to control chromatin accessibility Histone modifications such as H3K4me[3] and H3K9ac identify “active” transcriptional start sites (TSSs) and gene promoters, while others such as H3K4me[1] and H3K27ac identify distal regulatory elements (enhancers)[22]. Transcriptional responses are primed via the chromatin accessibility landscape in memory T cells

Methods

Results

Conclusion