Epigenetic induction of EGR-1 expression by the amyloid precursor protein during exposure to novelty

PLoS One. 2013 Sep 16;8(9):e74305. doi: 10.1371/journal.pone.0074305. eCollection 2013.

Abstract

Following transcriptome comparison of primary cultures isolated from brain of mice expressing or not the amyloid precursor protein APP, we found transcription of the EGR-1 gene to be regulated by APP. In primary cultures of cortical neurons, APP significantly down regulated EGR-1 expression at both mRNA and protein levels in a γ-secretase independent manner. The intracellular domain of APP did not interact with EGR-1 gene promoter, but enrichment of acetylated histone H4 at the EGR-1 promoter region was measured in APP-/- neurons, as well as in brain of APP-/- mice, in which increase in EGR-1 expression was also measured. These results argue for an important function of APP in the epigenetic regulation of EGR-1 gene transcription both in vitro and in vivo. In APP-/- mice, constitutive overexpression of EGR-1 in brain impaired epigenetic induction of this early transcriptional regulator during exposure to novelty. Altogether, these results indicate an important function of APP in the epigenetic regulation of the transcription of EGR-1, known to be important for memory formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / pharmacology*
  • Animals
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Early Growth Response Protein 1 / genetics*
  • Early Growth Response Protein 1 / metabolism
  • Epigenesis, Genetic / drug effects*
  • Female
  • Male
  • Mice
  • Real-Time Polymerase Chain Reaction

Substances

  • Amyloid beta-Protein Precursor
  • Early Growth Response Protein 1

Grants and funding

This work was supported by the Belgian Fonds pour la Recherche Scientifique (FNRS-FRS) and FRIA, by Interuniversity Attraction Poles Programme-Belgian State-Belgian Science Policy, The Belgian Fonds de la Recherche Scientifique Médicale, the Fondation pour la Recherche sur la Maladie d’Alzheimer (SAOFRMA) and the Programme d’excellence « Marshall » Diane convention. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.