The Il6 -39 kb enhancer containing clustered GATA2- and PU.1-binding sites is essential for Il6 expression in murine mast cells

Shin'ya Ohmori; Jun Takai; Satoshi Uemura; Akihito Otsuki; Tetsuya Mori; Kinuko Ohneda; Takashi Moriguchi

doi:10.1016/j.isci.2022.104942

The Il6 -39 kb enhancer containing clustered GATA2- and PU.1-binding sites is essential for Il6 expression in murine mast cells

iScience. 2022 Aug 14;25(9):104942. doi: 10.1016/j.isci.2022.104942. eCollection 2022 Sep 16.

Authors

Shin'ya Ohmori¹, Jun Takai², Satoshi Uemura², Akihito Otsuki³, Tetsuya Mori¹, Kinuko Ohneda³, Takashi Moriguchi²

Affiliations

¹ Department of Pharmacy, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan.
² Division of Medical Biochemistry, Tohoku Medical Pharmaceutical University, Sendai, Japan.
³ Division of Genomics and Disease Prevention, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

Abstract

Mast cells serve as a first-line defense of innate immunity. Interleukin-6 (IL-6) induced by bacterial lipopolysaccharide (LPS) in mast cells plays a crucial role in antibacterial protection. The zinc finger transcription factor GATA2 cooperatively functions with the ETS family transcription factor PU.1 in multiple mast cell activities. However, the regulatory landscape directed by GATA2 and PU.1 under inflammation remains elusive. We herein showed that a large proportion of GATA2-binding peaks were closely located with PU.1-binding peaks in distal cis-regulatory regions of inflammatory cytokine genes in mast cells. Notably, GATA2 and PU.1 played crucial roles in promoting LPS-mediated inflammatory cytokine production. Genetic ablation of GATA2-PU.1-clustered binding sites at the Il6 -39 kb region revealed its central role in LPS-induced Il6 expression in mast cells. We demonstrate a novel collaborative activity of GATA2 and PU.1 in cytokine induction upon inflammatory stimuli via the GATA2-PU.1 overlapping sites in the distal cis-regulatory regions.

Keywords: Immunology; Molecular biology; Molecular mechanism of gene regulation.