The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory

• Published in: Nature immunology Vol. 16; no. 10; pp. 1034 - 1043
• Main Authors: Yoshida, Keisuke, Maekawa, Toshio, Zhu, Yujuan, Renard-Guillet, Claire, Chatton, Bruno, Inoue, Kentaro, Uchiyama, Takeru, Ishibashi, Ken-ichi, Yamada, Takuji, Ohno, Naohito, Shirahige, Katsuhiko, Okada-Hatakeyama, Mariko, Ishii, Shunsuke
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2015; Nature Publishing Group
• Subjects: 45; 45/15; 45/61; 631/250/2502/2170; 64; 64/60; 692/699/249/2510/9; Activating Transcription Factors - genetics; Activating Transcription Factors - metabolism; Animals; Bacterial diseases; Biomedicine; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - immunology; Genetic aspects; Growth; Health aspects; Immune response; Immune system; Immunologic Memory - genetics; Immunologic Memory - immunology; Immunology; Infectious Diseases; Lipopolysaccharides - pharmacology; Lymphocytes; Macrophages; Macrophages - immunology; Mice; Reverse Transcriptase Polymerase Chain Reaction; Transcription factors
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3257

The role of the stress-induced transcription factor ATF7 in immunity is largely unknown. Ishii and colleagues show that ATF7 represses select innate immunity–related genes, but activity is downregulated during the induction of macrophage memory. Immunological memory is thought to be mediated exclusively by lymphocytes. However, enhanced innate immune responses caused by a previous infection increase protection against reinfection, which suggests the presence of innate immunological memory. Here we identified an important role for the stress-response transcription factor ATF7 in innate immunological memory. ATF7 suppressed a group of genes encoding factors involved in innate immunity in macrophages by recruiting the histone H3K9 dimethyltransferase G9a. Treatment with lipopolysaccharide, which mimics bacterial infection, induced phosphorylation of ATF7 via the kinase p38, which led to the release of ATF7 from chromatin and a decrease in repressive histone H3K9me2 marks. A partially disrupted chromatin structure and increased basal expression of target genes were maintained for long periods, which enhanced resistance to pathogens. ATF7 might therefore be important in controlling memory in cells of the innate immune system.