@article{0607f927f3fe4bdebaa6754964a4ed84,
title = "Rapid Enhancer Remodeling and Transcription Factor Repurposing Enable High Magnitude Gene Induction upon Acute Activation of NK Cells",
abstract = "Innate immune responses rely on rapid and precise gene regulation mediated by accessibility of regulatory regions to transcription factors (TFs). In natural killer (NK) cells and other innate lymphoid cells, competent enhancers are primed during lineage acquisition, and formation of de novo enhancers characterizes the acquisition of innate memory in activated NK cells and macrophages. Here, we investigated how primed and de novo enhancers coordinate to facilitate high-magnitude gene induction during acute activation. Epigenomic and transcriptomic analyses of regions near highly induced genes (HIGs) in NK cells both in vitro and in a model of Toxoplasma gondii infection revealed de novo chromatin accessibility and enhancer remodeling controlled by signal-regulated TFs STATs. Acute NK cell activation redeployed the lineage-determining TF T-bet to de novo enhancers, independent of DNA-sequence-specific motif recognition. Thus, acute stimulation reshapes enhancer function through the combinatorial usage and repurposing of both lineage-determining and signal-regulated TFs to ensure an effective response.",
keywords = "T-bet, Toxoplasma Gondii infection, de novo enhancers, innate lymphoid cells, lineage defining transcription factors, natural killer cells, poised enhancers, signal regulated transcription factors, signal transducer and activator of transcription (STAT) protein, super-enhancers",
author = "Giuseppe Scium{\`e} and Yohei Mikami and Dragana Jankovic and Hiroyuki Nagashima and Villarino, {Alejandro V.} and Tasha Morrison and Chen Yao and Sadie Signorella and Sun, {Hong Wei} and Brooks, {Stephen R.} and Difeng Fang and Vittorio Sartorelli and Shingo Nakayamada and Kiyoshi Hirahara and Beatrice Zitti and Davis, {Fred P.} and Yuka Kanno and O'Shea, {John J.} and Shih, {Han Yu}",
note = "Funding Information: We thank S. Dell'Orso, G. Gutierrez-Cruz (Genomic Technology Section, NIAMS), J. Simone, J. Lay, and K. Tinsley (Flow Cytometry Section, NIAMS) for their excellent technical support. We thank Dr. Nilisha Fernando for proofreading this manuscript. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH. This work was supported by the Intramural Research Programs of the NEI, NIAMS, and NIAID and the Italian Association for Cancer Research (AIRC) (MFAG 2018; project code 21311). Conceptualization, G.S. Y.K. J.J.O. and H.-Y.S.; Writing – Original Draft, G.S. J.J.O. and H.-Y.S.; Writing – Review & Editing, G.S. V.S. Y.K. J.J.O. and H.-Y.S.; Investigation, G.S. Y.M. D.J. H.N. A.V. T.M. C.Y. S.S. D.F. S.N. K.H. B.Z. Y.K. and H.-Y.S.; Formal Analysis, H.-W.S. S.R.B. F.P.D. and H.-Y.S. The authors declare no competing interests. Funding Information: We thank S. Dell{\textquoteright}Orso, G. Gutierrez-Cruz (Genomic Technology Section, NIAMS), J. Simone, J. Lay, and K. Tinsley (Flow Cytometry Section, NIAMS) for their excellent technical support. We thank Dr. Nilisha Fernando for proofreading this manuscript. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH. This work was supported by the Intramural Research Programs of the NEI , NIAMS , and NIAID and the Italian Association for Cancer Research (AIRC) (MFAG 2018; project code 21311 ). Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = oct,
day = "13",
doi = "10.1016/j.immuni.2020.09.008",
language = "English (US)",
volume = "53",
pages = "745--758.e4",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "4",
}