TY - JOUR
T1 - Rapid Enhancer Remodeling and Transcription Factor Repurposing Enable High Magnitude Gene Induction upon Acute Activation of NK Cells
AU - Sciumè, Giuseppe
AU - Mikami, Yohei
AU - Jankovic, Dragana
AU - Nagashima, Hiroyuki
AU - Villarino, Alejandro V.
AU - Morrison, Tasha
AU - Yao, Chen
AU - Signorella, Sadie
AU - Sun, Hong Wei
AU - Brooks, Stephen R.
AU - Fang, Difeng
AU - Sartorelli, Vittorio
AU - Nakayamada, Shingo
AU - Hirahara, Kiyoshi
AU - Zitti, Beatrice
AU - Davis, Fred P.
AU - Kanno, Yuka
AU - O'Shea, John J.
AU - Shih, Han Yu
N1 - 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’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:
© 2020
PY - 2020/10/13
Y1 - 2020/10/13
N2 - 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.
AB - 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.
KW - T-bet
KW - Toxoplasma Gondii infection
KW - de novo enhancers
KW - innate lymphoid cells
KW - lineage defining transcription factors
KW - natural killer cells
KW - poised enhancers
KW - signal regulated transcription factors
KW - signal transducer and activator of transcription (STAT) protein
KW - super-enhancers
UR - http://www.scopus.com/inward/record.url?scp=85092292833&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85092292833&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2020.09.008
DO - 10.1016/j.immuni.2020.09.008
M3 - Article
C2 - 33010223
AN - SCOPUS:85092292833
SN - 1074-7613
VL - 53
SP - 745-758.e4
JO - Immunity
JF - Immunity
IS - 4
ER -
