Priming of transcriptional memory responses via the chromatin accessibility landscape in T cells.
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.
Faculty of Education, Science, Technology &Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
Wen Juan
WJ
Tu
Faculty of Education, Science, Technology &Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
Kristine
K
Hardy
Faculty of Education, Science, Technology &Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
Christopher R
CR
Sutton
Faculty of Education, Science, Technology &Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
Robert
R
McCuaig
Department of Microbiology, Biomedical Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.|Department of Microbiology &Immunology, The Doherty Institute for Infection and Immunity, University of Melbourne, Victoria 3010, Australia.
Jasmine
J
Li
Faculty of Education, Science, Technology &Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
Jenny
J
Dunn
Faculty of Education, Science, Technology &Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
Abel
A
Tan
INSERM U955 Eq16 Faculte de medicine Henri Mondor and Universite Paris-Est, Creteil/Vaccine Research Institute, Creteil 94010, France.
Vedran
V
Brezar
Faculty of Education, Science, Technology &Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
Melanie
M
Morris
School of Molecular Bioscience, The University of Sydney, Sydney, NSW, Australia.
Gareth
G
Denyer
QIMR Berghofer Centre for Immunotherapy and Vaccine Development QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.|Tumour Immunology Laboratory, Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Sau Kuen
SK
Lee
Department of Microbiology, Biomedical Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.|Department of Microbiology &Immunology, The Doherty Institute for Infection and Immunity, University of Melbourne, Victoria 3010, Australia.
Stephen J
SJ
Turner
INSERM U955 Eq16 Faculte de medicine Henri Mondor and Universite Paris-Est, Creteil/Vaccine Research Institute, Creteil 94010, France.
Nabila
N
Seddiki
QIMR Berghofer Centre for Immunotherapy and Vaccine Development QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.|Tumour Immunology Laboratory, Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Corey
C
Smith
QIMR Berghofer Centre for Immunotherapy and Vaccine Development QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.|Tumour Immunology Laboratory, Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Rajiv
R
Khanna
Faculty of Education, Science, Technology &Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
Sudha
S
Rao
D000107:Acetylation; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002843:Chromatin / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D050980:GATA Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D050778:NFATC Transcription Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014158:Transcription, Genetic
D002843:Chromatin; D050980:GATA Transcription Factors; D006657:Histones; D050778:NFATC Transcription Factors