Tu, Wen JuanHardy, KristineSutton, Christopher R.McCuaig, RobertLi, JasmineDunn, JennyTan, AbelBrezar, VedranMorris, MelanieDenyer, GarethLee, Sau KuenTurner, Stephen J.Seddiki, NabilaSmith, CoreyKhanna, RajivRao, Sudha2025-12-172025-12-172045-2322PubMed:28317936ORCID:/0000-0003-1660-4477/work/182749138https://hdl.handle.net/1885/733796232Memory 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.enPublisher Copyright: © The Author(s) 2017.2017-03-2010.1038/srep4482585015979801