title: Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain.
abstract: Epigenetic processes such as DNA methylation have been implicated in the pathophysiology of neurodevelopmental disorders including schizophrenia and autism. Epigenetic changes can be induced by environmental exposures such as inflammation. Here we tested the hypothesis that prenatal inflammation, a recognized risk factor for schizophrenia and related neurodevelopmental conditions, alters DNA methylation in key brain regions linked to schizophrenia, namely the dopamine rich striatum and endocrine regulatory centre, the hypothalamus. DNA methylation across highly repetitive elements (long interspersed element 1 (LINE1) and intracisternal A-particles (IAPs)) were used to proxy global DNA methylation. We also investigated the Mecp2 gene because it regulates transcription of LINE1 and has a known association with neurodevelopmental disorders. Brain tissue was harvested from 6 week old offspring of mice exposed to the viral analog PolyI:C or saline on gestation day 9. We used Sequenom EpiTYPER assay to quantitatively analyze differences in DNA methylation at IAPs, LINE1 elements and the promoter region of Mecp2. In the hypothalamus, prenatal exposure to PolyI:C caused significant global DNA hypomethylation (t=2.44, P=0.019, PolyI:C mean 69.67%, saline mean 70.19%), especially in females, and significant hypomethylation of the promoter region of Mecp2, (t=3.32, P=0.002; PolyI:C mean 26.57%, saline mean 34.63%). IAP methylation was unaltered. DNA methylation in the striatum was not significantly altered. This study provides the first experimental evidence that exposure to inflammation during prenatal life is associated with epigenetic changes, including Mecp2 promoter hypomethylation. This suggests that environmental and genetic risk factors associated with neurodevelopmental disorders may act upon similar pathways. This is important because epigenetic changes are potentially modifiable and their investigation may open new avenues for treatment.
authors.affiliation: Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: P
authors.initials: P
authors.lastname: Basil
authors.affiliation: Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.affiliation: University of Exeter Medical School, Exeter University, Exeter, UK.
authors.forename: E L
authors.initials: EL
authors.lastname: Dempster
authors.affiliation: 1] University of Exeter Medical School, Exeter University, Exeter, UK [2] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Mill
authors.affiliation: 1] Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong SAR, China [2] Centre for Genomic Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: P-C
authors.initials: PC
authors.lastname: Sham
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
authors.forename: C C Y
authors.initials: CC
authors.lastname: Wong
authors.affiliation: 1] Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong SAR, China [2] Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King's College London, London, UK.
authors.forename: G M
authors.initials: GM
authors.lastname: McAlonan
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000196:embryology* / Q000276:immunology*; D003342:Corpus Striatum / Q000196:embryology / Q000276:immunology; D019175:DNA Methylation / Q000235:genetics* / Q000276:immunology*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000235:genetics* / Q000276:immunology*; D005260:Female; D007031:Hypothalamus / Q000196:embryology / Q000276:immunology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000276:immunology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000276:immunology*; D012016:Reference Values; D012737:Sex Factors
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D011070:Poly I-C