TY - JOUR
T1 - Priming of transcriptional memory responses via the chromatin accessibility landscape in T cells
AU - TU, Sherry
AU - HARDY, Kris
AU - SUTTON, Chris
AU - McCuaig, Robert
AU - Li, Jasmine
AU - DUNN, Jenny
AU - Tan, Abel
AU - Brezar, Vedran
AU - Morris, Melanie
AU - Denyer, Gareth
AU - Lee, Sau
AU - Turner, Stephen J.
AU - Seddiki, Nabila
AU - Smith, Corey
AU - Khanna, Rajiv
AU - RAO, Sudha
PY - 2017/3/20
Y1 - 2017/3/20
N2 - 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.
AB - 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.
KW - Acetylation
KW - Binding Sites
KW - CD4-Positive T-Lymphocytes/immunology
KW - Chromatin/genetics
KW - Chromatin Assembly and Disassembly
KW - GATA Transcription Factors/metabolism
KW - Gene Expression Profiling
KW - Histones/metabolism
KW - Humans
KW - Immunologic Memory/genetics
KW - Lymphocyte Activation/genetics
KW - NFATC Transcription Factors/metabolism
KW - Promoter Regions, Genetic
KW - Protein Binding
KW - T-Lymphocytes/immunology
KW - Transcription, Genetic
UR - http://www.scopus.com/inward/record.url?scp=85015979801&partnerID=8YFLogxK
UR - http://www.mendeley.com/research/priming-transcriptional-memory-responses-via-chromatin-accessibility-landscape-t-cells
U2 - 10.1038/srep44825
DO - 10.1038/srep44825
M3 - Article
C2 - 28317936
SN - 2045-2322
VL - 7
SP - 1
EP - 20
JO - Scientific Reports
JF - Scientific Reports
M1 - 44825
ER -