Prenatal immune activation alters the adult neural epigenome but can be partly stabilised by a n-3 polyunsaturated fatty acid diet.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620847
Title:
Prenatal immune activation alters the adult neural epigenome but can be partly stabilised by a n-3 polyunsaturated fatty acid diet.
Authors:
Basil, P.; Li, Q.; Gui, H.; Hui, T. C. K.; Ling, V. H. M.; Wong, C. C. Y.; Mill, Jonathan; McAlonan, G. M.; Sham, P-C
Abstract:
An unstable epigenome is implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism. This is important because the epigenome is potentially modifiable. We have previously reported that adult offspring exposed to maternal immune activation (MIA) prenatally have significant global DNA hypomethylation in the hypothalamus. However, what genes had altered methylation state, their functional effects on gene expression and whether these changes can be moderated, have not been addressed. In this study, we used next-generation sequencing (NGS) for methylome profiling in a MIA rodent model of neurodevelopmental disorders. We assessed whether differentially methylated regions (DMRs) affected the chromatin state by mapping known DNase I hypersensitivity sites (DHSs), and selected overlapping genes to confirm a functional effect of MIA on gene expression using qPCR. Finally, we tested whether methylation differences elicited by MIA could be limited by post-natal dietary (omega) n-3 polyunsaturated fatty acid (PUFA) supplementation. These experiments were conducted using hypothalamic brain tissue from 12-week-old offspring of mice injected with viral analogue PolyI:C on gestation day 9 of pregnancy or saline on gestation day 9. Half of the animals from each group were fed a diet enriched with n-3 PUFA from weaning (MIA group, n = 12 units, n = 39 mice; Control group, n = 12 units, n = 38 mice). The results confirmed our previous finding that adult offspring exposed to MIA prenatally had significant global DNA hypomethylation. Furthermore, genes linked to synaptic plasticity were over-represented among differentially methylated genes following MIA. More than 80% of MIA-induced hypomethylated sites, including those affecting chromatin state and MECP2 binding, were stabilised by the n-3 PUFA intervention. MIA resulted in increased expression of two of the 'top five' genes identified from an integrated analysis of DMRs, DHSs and MECP2 binding sites, namely Abat (t = 2.46, p < 0.02) and Gnas9 (t = 2.96, p < 0.01), although these changes were not stabilised by dietary intervention. Thus, prenatal MIA exposure impacts upon the epigenomic regulation of gene pathways linked to neurodevelopmental conditions; and many of the changes can be attenuated by a low-cost dietary intervention.
Citation:
Prenatal immune activation alters the adult neural epigenome but can be partly stabilised by a n-3 polyunsaturated fatty acid diet. 2018, 8 (1):125 Transl Psychiatry
Publisher:
Nature
Journal:
Translational psychiatry
Issue Date:
2-Jul-2018
URI:
http://hdl.handle.net/11287/620847
DOI:
10.1038/s41398-018-0167-x
PubMed ID:
29967385
Additional Links:
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29967385/
Type:
Journal Article
Language:
en
ISSN:
2158-3188
Appears in Collections:
Honorary contracts publications; 2018 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorBasil, P.en
dc.contributor.authorLi, Q.en
dc.contributor.authorGui, H.en
dc.contributor.authorHui, T. C. K.en
dc.contributor.authorLing, V. H. M.en
dc.contributor.authorWong, C. C. Y.en
dc.contributor.authorMill, Jonathanen
dc.contributor.authorMcAlonan, G. M.en
dc.contributor.authorSham, P-Cen
dc.date.accessioned2018-10-04T09:44:34Z-
dc.date.available2018-10-04T09:44:34Z-
dc.date.issued2018-07-02-
dc.identifier.citationPrenatal immune activation alters the adult neural epigenome but can be partly stabilised by a n-3 polyunsaturated fatty acid diet. 2018, 8 (1):125 Transl Psychiatryen
dc.identifier.issn2158-3188-
dc.identifier.pmid29967385-
dc.identifier.doi10.1038/s41398-018-0167-x-
dc.identifier.urihttp://hdl.handle.net/11287/620847-
dc.description.abstractAn unstable epigenome is implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism. This is important because the epigenome is potentially modifiable. We have previously reported that adult offspring exposed to maternal immune activation (MIA) prenatally have significant global DNA hypomethylation in the hypothalamus. However, what genes had altered methylation state, their functional effects on gene expression and whether these changes can be moderated, have not been addressed. In this study, we used next-generation sequencing (NGS) for methylome profiling in a MIA rodent model of neurodevelopmental disorders. We assessed whether differentially methylated regions (DMRs) affected the chromatin state by mapping known DNase I hypersensitivity sites (DHSs), and selected overlapping genes to confirm a functional effect of MIA on gene expression using qPCR. Finally, we tested whether methylation differences elicited by MIA could be limited by post-natal dietary (omega) n-3 polyunsaturated fatty acid (PUFA) supplementation. These experiments were conducted using hypothalamic brain tissue from 12-week-old offspring of mice injected with viral analogue PolyI:C on gestation day 9 of pregnancy or saline on gestation day 9. Half of the animals from each group were fed a diet enriched with n-3 PUFA from weaning (MIA group, n = 12 units, n = 39 mice; Control group, n = 12 units, n = 38 mice). The results confirmed our previous finding that adult offspring exposed to MIA prenatally had significant global DNA hypomethylation. Furthermore, genes linked to synaptic plasticity were over-represented among differentially methylated genes following MIA. More than 80% of MIA-induced hypomethylated sites, including those affecting chromatin state and MECP2 binding, were stabilised by the n-3 PUFA intervention. MIA resulted in increased expression of two of the 'top five' genes identified from an integrated analysis of DMRs, DHSs and MECP2 binding sites, namely Abat (t = 2.46, p < 0.02) and Gnas9 (t = 2.96, p < 0.01), although these changes were not stabilised by dietary intervention. Thus, prenatal MIA exposure impacts upon the epigenomic regulation of gene pathways linked to neurodevelopmental conditions; and many of the changes can be attenuated by a low-cost dietary intervention.en
dc.language.isoenen
dc.publisherNatureen
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29967385/en
dc.rightsArchived with thanks to Translational psychiatryen
dc.subjectWessex Classification Subject Headings::Mental healthen
dc.titlePrenatal immune activation alters the adult neural epigenome but can be partly stabilised by a n-3 polyunsaturated fatty acid diet.en
dc.typeJournal Articleen
dc.identifier.journalTranslational psychiatryen
dc.type.versionPublisheden

Related articles on PubMed

All Items in RD&E Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.