Transcription factor IRF8 shapes microglia transcriptome profiles Richard Pan1, Mahesh Bachu1, Anup Dey1, Keita Saeki1and Keiko Ozato1 1Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, 20892, USA
Interferon regulatory factor 8 (IRF8) is a transcription factor expressed in myeloid lineage cells that plays important roles in their differentiation and function. Within the central nervous system IRF8 localizes to microglia, the primary immune cells that function as “resident macrophages”. Recent studies have implicated microglia as key players in the development and progression of neurodegenerative disease and identified an altered microglial transcriptome during disease. Previous work from the lab showed that IRF8 critically regulates neuroinflammatory disease such as multiple sclerosis. Here, we sought to study microglial transcriptomes from wild type and IRF8-/- (knockout, KO) mice by RNA-seq analysis. We found that IRF8 KO microglia display a dramatically altered transcriptome profile as compared to wild type microglia profile. IRF8 KO microglia exhibited upregulation of many genes involved in cell proliferation and downregulation of several lysosomal enzymes. Interestingly, cholesterol metabolism also appeared to be affected as several genes including APOE were significantly upregulated in IRF8 KO microglia. APOE has long been linked to the development of Alzheimer's Disease (AD) and was recently shown to be a hallmark of microglia during neurodegeneration. Further analysis of several other genes indicated a correlation between AD and IRF8 KO. These results may suggest a possible causal relation between IRF8 KO and disease whereby alteration of IRF8 expression may play a role in the progression of neurodegenerative conditions.
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