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Safeguard function of PU.1 shapes the inflammatory epigenome of neutrophils

Item Type:Article
Title:Safeguard function of PU.1 shapes the inflammatory epigenome of neutrophils
Creators Name:Fischer, J. and Walter, C. and Tönges, A. and Aleth, H. and Costa Jordão, M.J. and Leddin, M. and Gröning, V. and Erdmann, T. and Lenz, G. and Roth, J. and Vogl, T. and Prinz, M. and Dugas, M. and Jacobsen, I.D. and Rosenbauer, F.
Abstract:Neutrophils are essential first-line defense cells against invading pathogens, yet when inappropriately activated, their strong immune response can cause collateral tissue damage and contributes to immunological diseases. However, whether neutrophils can intrinsically titrate their immune response remains unknown. Here we conditionally deleted the Spi1 gene, which encodes the myeloid transcription factor PU.1, from neutrophils of mice undergoing fungal infection and then performed comprehensive epigenomic profiling. We found that as well as providing the transcriptional prerequisite for eradicating pathogens, the predominant function of PU.1 was to restrain the neutrophil defense by broadly inhibiting the accessibility of enhancers via the recruitment of histone deacetylase 1. Such epigenetic modifications impeded the immunostimulatory AP-1 transcription factor JUNB from entering chromatin and activating its targets. Thus, neutrophils rely on a PU.1-installed inhibitor program to safeguard their epigenome from undergoing uncontrolled activation, protecting the host against an exorbitant innate immune response.
Keywords:Candida albicans, Candidiasis, Disease Resistance, Epigenomics, Gene Expression Profiling, Genetic Epigenesis, Inbred C57BL Mice, Knockout Mice, Neutrophils, Proto-Oncogene Proteins, Survival Analysis, Trans-Activators, Transcriptome, Transgenic Mice, Animals, Mice
Source:Nature Immunology
Publisher:Nature Publishing Group
Page Range:546-558
Date:May 2019
Official Publication:https://doi.org/10.1038/s41590-019-0343-z
PubMed:View item in PubMed

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