摘要：Genetic association studies have identified multiple variants at the
SPI1 locus that modify risk and age of onset for Alzheimer’s Disease (AD). Reports linking risk variants to gene expression suggest that variants denoting higher
SPI1 expression are likely to have an earlier AD onset, and several other AD risk genes contain PU.1 binding sites in the promoter region. Overall, this suggests the level of
SPI1 may alter microglial phenotype potentially impacting AD. This study determined how the microglial transcriptome was altered following modest changes to
Spi1 expression in primary mouse microglia. RNA-sequencing was performed on microglia with reduced or increased
Spi1/PU.1 expression to provide an unbiased approach to determine transcriptomic changes affected by
Spi1. In summary, a reduction in microglial
Spi1 resulted in the dysregulation of transcripts encoding proteins involved in DNA replication pathways while an increased
Spi1 results in an upregulation of genes associated with immune response pathways. Additionally, a subset of 194
Spi1 dose-sensitive genes was identified and pathway analysis suggests that several innate immune and interferon response pathways are impacted by the concentration of
Spi1. Together these results suggest
Spi1 levels can alter the microglial transcriptome and suggests interferon pathways may be altered in individuals with AD related
Spi1 risk SNPs.
