Transcriptional Activation of the TREM2 Gene by ZEB2 in a Zinc Finger-Dependent Manner

<b>Background/Objectives</b>: TREM2 is a transmembrane receptor highly expressed in microglia and macrophages, and its involvement in Alzheimer's disease, obesity, and cancer has garnered significant attention. Although its biological function has been actively investigated, the mechanisms by which its expression is regulated remain incompletely characterized. In this study, we aimed to identify transcription factors that modulate TREM2 expression among those reported to be expressed in microglia. <b>Methods</b>: We inserted a 5 kb upstream region of <i>TREM2</i> into a luciferase reporter vector. This construct was co-expressed with 15 transcription factors, and the <i>TREM2</i> transcriptional activity was evaluated using luciferase assays. The most promising transcription factor was subsequently knocked down in HMC3 cells, which are derived from human microglia, to assess its effect on endogenous <i>TREM2</i> expression. <b>Results</b>: Among the 15 transcription factor candidates tested, SPI1 (PU.1), MAFB, CEBPA, ZEB2, and SALL1 most strongly enhanced <i>TREM2</i> transcriptional activity. ZEB2 was prioritized due to its limited study in microglia and higher co-expression with <i>TREM2</i>. In HMC3 cells, ZEB2 knockdown reduced both <i>TREM2</i> mRNA and protein levels. Further analysis using domain-deleted mutants of ZEB2 indicated that the zinc finger domains are essential for its transcriptional activity. Analysis using truncated mutants of the <i>TREM2</i> upstream region suggests that ZEB2 acts on multiple sites within this region. Chromatin immunoprecipitation also suggested an interaction between ZEB2 and the upstream region of <i>TREM2</i>. <b>Conclusions</b>: This study novelly suggests ZEB2 as a transcription factor that promotes TREM2 expression. Further investigation into the role of ZEB2 in various TREM2-associated diseases is warranted.