Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer's disease

J Biol Chem. 2023 May;299(5):104688. doi: 10.1016/j.jbc.2023.104688. Epub 2023 Apr 11.

Abstract

TREM2 encoding 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 in TREM2 may significantly increase the risk of AD by promoting AD pathologies. However, how the expression of TREM2 is regulated and the transcription factors required for TREM2 expression are largely unknown. By luciferase assay, DNA pull-down, and in silico predictions, we identified Yin Yang 1(YY1) as a binding protein of the minimal promoter of the TREM2 gene, and the binding was further confirmed by EMSA and DNA pull-down assay. shRNA-mediated YY1 silencing significantly reduced the activity of the TREM2 minimal 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 of TREM2 expression. Our study suggests that microglial YY1 could be targeted to maintain TREM2 expression for AD prevention and therapy.

Keywords: Alzheimer’s disease; TREM2; YY1; gene regulation; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / metabolism
  • Animals
  • Brain / metabolism
  • Cell Line
  • Lipopolysaccharides / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Microglia / metabolism
  • Receptors, Immunologic* / genetics
  • Receptors, Immunologic* / metabolism
  • YY1 Transcription Factor* / genetics
  • YY1 Transcription Factor* / metabolism

Substances

  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • YY1 Transcription Factor