Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Saunderson, Emily A., Spiers, Helen, Mifsud, Karen R., Gutierrez-Mecinas, Maria, Trollope, Alexandra F., Shaikh, Abeera, Mill, Jonathan, and Reul, Johannes M.H.M. (2016) Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus. Proceedings of the National Academy of Sciences of the United States of America, 113 (17). pp. 4830-4835.

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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.

Item ID: 43659
Item Type: Article (Research - C1)
ISSN: 1091-6490
Keywords: stress, behavior, DNA methylation, immediate-early gene, hippocampus
Funders: Biotechnology and Biological Sciences Research Council (BBSRC), Medical Research Council (MRC), British Pharmacological Society
Projects and Grants: BBSCR Grant BB/K007408/1, BBSCR Grant BB/G02507X/1
Date Deposited: 02 Jun 2016 00:17
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3209 Neurosciences > 320903 Central nervous system @ 50%
31 BIOLOGICAL SCIENCES > 3105 Genetics > 310504 Epigenetics (incl. genome methylation and epigenomics) @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920111 Nervous System and Disorders @ 100%
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