TREM2encoding the transmembrane receptor protein TREM2 is a risk gene of Alzheimer’s disease (AD), and the impairment of TREM2 functions in microglia due to mutations inTREM2may significantly increase the risk of AD by promoting AD pathologies. However, how the expression ofTREM2is regulated and the transcription factors required forTREM2expression are largely unknown. By luciferase assay, DNA pull-down, andin silicopredictions, we identified Yin Yang 1(YY1) as a binding protein of the minimal promoter of theTREM2gene, and the binding was further confirmed by EMSA and DNA pull-down assay. shRNA-mediatedYY1silencing significantly reduced the activity of theTREM2minimal promoter and TREM2 protein levels in the microglial cell line BV2 and the neuroblastoma Neuro2A. Furthermore, we found that the levels of TREM2 and YY1 were both downregulated in lipopolysaccharide-treated BV2 cells and in the brain of AD model mice. These results demonstrated that YY1 plays a crucial role in the regulation ofTREM2expression. Our study suggests that microglial YY1 could be targeted to maintainTREM2expression for AD prevention and therapy.