Rapid Enhancer Remodeling and Transcription Factor Repurposing Enable High Magnitude Gene Induction upon Acute Activation of NK Cells

Giuseppe Sciumè, Yohei Mikami, Dragana Jankovic, Hiroyuki Nagashima, Alejandro V. Villarino, Tasha Morrison, Chen Yao, Sadie Signorella, Hong Wei Sun, Stephen R. Brooks, Difeng Fang, Vittorio Sartorelli, Shingo Nakayamada, Kiyoshi Hirahara, Beatrice Zitti, Fred P. Davis, Yuka Kanno, John J. O'Shea, Han Yu Shih

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)745-758.e4
JournalImmunity
Volume53
Issue number4
DOIs
Publication statusPublished - 2020 Oct 13

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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