title: Epigenetic changes at gene promoters in response to immune activation in utero.
abstract: Increasing evidence suggests that maternal infection increases the risk of psychiatric disorders, such as schizophrenia and autism in offspring. However, the molecular mechanisms associated with these effects are unclear. Here, we have studied epigenetic gene regulation in mice exposed to non-specific immune activation elicited by polyI:C injection to pregnant dams. Using Western blot analysis, we detected global hypoacetylation of histone H3, at lysine residues 9 and 14, and histone H4, at lysine residue 8, in the cortex from juvenile (∼24days of age) offspring exposed to polyI:C in utero, but not from adult (3months of age) offspring, which exhibit significant behavioral abnormalities. Accordingly, we detected robust deficits in the expression of genes associated with neuronal development, synaptic transmission and immune signaling in the cortex of polyI:C-exposed juvenile mice. In particular, we found that several genes in the glutamate receptor signaling pathway, including Gria1 and Slc17a7, showed decreases in promoter-specific histone acetylation, and corresponding gene expression deficits, in polyI:C-exposed offspring at both juvenile and adult ages. In contrast, the expression of these same genes, in addition to Disc1 and Ntrk3, was elevated in the hippocampus of juvenile mice, in concordance with elevated levels of promoter-specific histone acetylation. We suggest that these early epigenetic changes contribute to the delayed behavioral abnormalities that are observed in adult animals after exposure to polyI:C, and which resemble symptoms seen in schizophrenia and related disorders.
authors: Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Red., La Jolla, CA 92037, United States.
authors: Bin
authors: B
authors: Tang
authors: Haiqun
authors: H
authors: Jia
authors: Ryan J
authors: RJ
authors: Kast
authors: Elizabeth A
authors: EA
authors: Thomas
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D011070:Poly I-C; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology*; D012559:Schizophrenia / Q000276:immunology / Q000378:metabolism
chemical_list: D011070:Poly I-C