title: Epigenetic regulations of immediate early genes expression involved in memory formation by the amyloid precursor protein of Alzheimer disease.
abstract: We previously demonstrated that APP epigenetically regulates Egr1 expression both in cultured neurons and in vivo. Since Egr1 is an immediate early gene involved in memory formation, we wondered whether other early genes involved in memory were regulated by APP and we studied molecular mechanisms involved. By comparing prefrontal (PF) cortex from wild type (APP+/+) and APP knockout mice (APP-/-), we observed that APP down regulates expression of four immediate early genes, Egr1, c-Fos, Bdnf and Arc. Down regulation of Egr1, c-Fos and Bdnf transcription resulted from a decreased enrichment of acetylated histone H4 on the corresponding gene promoter. Further characterization of H4 acetylation at Egr1 and c-Fos promoters revealed increased acetylation of H4K5 and H4K12 residues in APP-/- mice. Whereas APP affected Egr1 promoter activity by reducing access of the CREB transcription factor, its effect on c-Fos appeared to depend on increased recruitment of HDAC2 histone deacetylase to the gene promoter. The physiological relevance of the epigenetic regulation of Egr1 and c-Fos gene transcription by APP was further analyzed following exposure of mice to novelty. Although transcription of Egr1 and c-Fos was increased following exposure of APP+/+ mice to novelty, such an induction was not possible in APP-/- mice with a high basal level of expression of these immediate early genes. Altogether, these results demonstrate that APP-mediated regulation of c-Fos and Egr1 by different epigenetic mechanisms is needed for their induction during exposure to novelty.
authors.affiliation: Alzheimer Dementia, Institute of Neurosciences (IoNS), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hendrickx
authors.affiliation: Alzheimer Dementia, Institute of Neurosciences (IoNS), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pierrot
authors.affiliation: Alzheimer Dementia, Institute of Neurosciences (IoNS), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Tasiaux
authors.affiliation: Cell Physiology, Institute of Neurosciences (IoNS), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schakman
authors.affiliation: Alzheimer Dementia, Institute of Neurosciences (IoNS), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: Kienlen-Campard
authors.affiliation: Genetic & Epigenetic Alterations in Genomes, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Charles
authors.initials: C
authors.lastname: De Smet
authors.affiliation: Alzheimer Dementia, Institute of Neurosciences (IoNS), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Octave
mesh_terms: D000107:Acetylation; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D051766:Early Growth Response Protein 1 / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D006657:Histones / Q000378:metabolism; D006801:Humans; D008568:Memory; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D006657:Histones