Transcriptional regulation of microglia priming by IRF7, IRF9 and SMAD3 in accelerated aging mice [ATAC-seq]

Microglia are the tissue resident macrophages of the central nervous system (CNS). Dysregulation of inflammatory processes in the CNS is associated with aging, and neurodegenerative diseases, where microglia acquire a sensitized, or primed, phenotype, which is characterized by an increased inflammatory phenotype and an exaggerated reactivity to immune challenges. Transcriptomic profiling of microglia in different neurodegenerative disease and aging mouse models identified a common, primed, gene expression signature. However, the transcriptional mechanisms that mediate microglia priming still remains unclear. In DNA repair deficient (Ercc1?/ko) mice, microglia acquire a profound primed phenotype and by integrating RNA-seq and ATAC-seq data of Ercc1?/ko microglia, we identified transcription factors IRF7, IRF9 and SMAD3 as possible core regulators of microglia priming. Our data suggest that increased IRF7/IRF9 activity and decreased SMAD3 activity might be important for microglia to acquire a primed gene signature. This study provides insight in the transcriptomic regulation of primed microglia, which are implicated in aging and neurodegenerative diseases. Overall design: ATAC sequencing analysis of FACS-isolated microglia from whole brains of Ercc1 KO and control mice at different ages (6-, 12-week-old). N = 2 per condition.