title: Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus.
abstract: Stressful events evoke long-term changes in behavioral responses; however, the underlying mechanisms in the brain are not well understood. Previous work has shown that epigenetic changes and immediate-early gene (IEG) induction in stress-activated dentate gyrus (DG) granule neurons play a crucial role in these behavioral responses. Here, we show that an acute stressful challenge [i.e., forced swimming (FS)] results in DNA demethylation at specific CpG (5'-cytosine-phosphate-guanine-3') sites close to the c-Fos (FBJ murine osteosarcoma viral oncogene homolog) transcriptional start site and within the gene promoter region of Egr-1 (early growth response protein 1) specifically in the DG. Administration of the (endogenous) methyl donor S-adenosyl methionine (SAM) did not affect CpG methylation and IEG gene expression at baseline. However, administration of SAM before the FS challenge resulted in an enhanced CpG methylation at the IEG loci and suppression of IEG induction specifically in the DG and an impaired behavioral immobility response 24 h later. The stressor also specifically increased the expression of the de novo DNA methyltransferase Dnmt3a [DNA (cytosine-5-)-methyltransferase 3 alpha] in this hippocampus region. Moreover, stress resulted in an increased association of Dnmt3a enzyme with the affected CpG loci within the IEG genes. No effects of SAM were observed on stress-evoked histone modifications, including H3S10p-K14ac (histone H3, phosphorylated serine 10 and acetylated lysine-14), H3K4me3 (histone H3, trimethylated lysine-4), H3K9me3 (histone H3, trimethylated lysine-9), and H3K27me3 (histone H3, trimethylated lysine-27). We conclude that the DNA methylation status of IEGs plays a crucial role in FS-induced IEG induction in DG granule neurons and associated behavioral responses. In addition, the concentration of available methyl donor, possibly in conjunction with Dnmt3a, is critical for the responsiveness of dentate neurons to environmental stimuli in terms of gene expression and behavior.
authors.affiliation: Neuro-Epigenetics Research Group, University of Bristol, Bristol BS1 3NY, United Kingdom;
authors.forename: Emily A
authors.initials: EA
authors.lastname: Saunderson
authors.affiliation: Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom;
authors.forename: Helen
authors.initials: H
authors.lastname: Spiers
authors.affiliation: Neuro-Epigenetics Research Group, University of Bristol, Bristol BS1 3NY, United Kingdom;
authors.forename: Karen R
authors.identifier: http://orcid.org/0000-0003-0848-935X
authors.initials: KR
authors.lastname: Mifsud
authors.affiliation: Neuro-Epigenetics Research Group, University of Bristol, Bristol BS1 3NY, United Kingdom;
authors.forename: Maria
authors.initials: M
authors.lastname: Gutierrez-Mecinas
authors.affiliation: Neuro-Epigenetics Research Group, University of Bristol, Bristol BS1 3NY, United Kingdom;
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Trollope
authors.affiliation: Neuro-Epigenetics Research Group, University of Bristol, Bristol BS1 3NY, United Kingdom;
authors.forename: Abeera
authors.initials: A
authors.lastname: Shaikh
authors.affiliation: Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom; University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: Neuro-Epigenetics Research Group, University of Bristol, Bristol BS1 3NY, United Kingdom; Hans.Reul@bristol.ac.uk.
authors.forename: Johannes M H M
authors.initials: JM
authors.lastname: Reul
mesh_terms: D000818:Animals; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects; D016762:Genes, fos; D042421:Histone Code / Q000187:drug effects; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D013312:Stress, Physiological / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics*; D013550:Swimming
chemical_list: D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D012436:S-Adenosylmethionine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNA methylation; behavior; hippocampus; immediate-early gene; stress