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

Sherry TU, Kris HARDY, Chris SUTTON, Robert McCuaig, Jasmine Li, Jenny DUNN, Abel Tan, Vedran Brezar, Melanie Morris, Gareth Denyer, Sau Lee, Stephen J. Turner, Nabila Seddiki, Corey Smith, Rajiv Khanna, Sudha RAO

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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, NF-κ B, 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.

Original languageEnglish
Article number44825
Pages (from-to)1-20
Number of pages20
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 20 Mar 2017

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    TU, S., HARDY, K., SUTTON, C., McCuaig, R., Li, J., DUNN, J., Tan, A., Brezar, V., Morris, M., Denyer, G., Lee, S., Turner, S. J., Seddiki, N., Smith, C., Khanna, R., & RAO, S. (2017). Priming of transcriptional memory responses via the chromatin accessibility landscape in T cells. Scientific Reports, 7, 1-20. [44825]. https://doi.org/10.1038/srep44825