Rescue of Aging-associated Decline in Dnmt3a2 Expression Restores Cognitive Abilities

Overview

Journal Nat Neurosci

Date 2012 Jul 4

PMID 22751036

Citations 139

Authors

Ana M M Oliveira

Thekla J Hemstedt

Hilmar Bading

Affiliations

Soon will be listed here.

Abstract

Cognitive abilities decline in normal aging, yet the underlying molecular mechanisms are poorly understood. We found that aging was associated with a decrease in the expression of the DNA methyltransferase Dnmt3a2 in the hippocampus and that rescuing Dnmt3a2 levels restored cognitive functions. Moreover, we found that Dnmt3a2 is an activity-regulated immediate early gene that is partly dependent on nuclear calcium signaling and that hippocampal Dnmt3a2 levels determine cognitive abilities in both young adult and aged mice.

Citing Articles

DNA methylation, histone acetylation in the regulation of memory and its modulation during aging.

Singh P, Paramanik V Front Aging. 2025; 5():1480932.

PMID: 39835300 PMC: 11743476. DOI: 10.3389/fragi.2024.1480932.

DNA Methylation and Histone Acetylation Contribute to the Maintenance of LTP in the Withdrawal Behavior Interneurons in Terrestrial Snails.

Zuzina A, Kolotova D, Balaban P Cells. 2024; 13(22).

PMID: 39594599 PMC: 11592888. DOI: 10.3390/cells13221850.

Study on the Role of Expression in the Dentate Gyrus of the Hippocampus in Reward Memory.

Zheng X, Ma R, He E, Peng X, Ma W, Zhang X Alpha Psychiatry. 2024; 25(5):641-647.

PMID: 39553491 PMC: 11562246. DOI: 10.5152/alphapsychiatry.2024.241602.

Enhancement of physiology via adaptive transcription.

Lissek T Pflugers Arch. 2024; 477(2):187-199.

PMID: 39482558 PMC: 11761519. DOI: 10.1007/s00424-024-03037-5.

Signal B, Phipps A, Giles K, Huskins S, Mercer T, Robinson M Cells. 2024; 13(16).

PMID: 39195281 PMC: 11353134. DOI: 10.3390/cells13161393.

References

Chen T, Ueda Y, Xie S, Li E . A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation. J Biol Chem. 2002; 277(41):38746-54. DOI: 10.1074/jbc.M205312200. View

Vanyushin B, Nemirovsky L, Klimenko V, Vasiliev V, BELOZERSKY A . The 5-methylcytosine in DNA of rats. Tissue and age specificity and the changes induced by hydrocortisone and other agents. Gerontologia. 1973; 19(3):138-52. View

Klose R, Bird A . Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006; 31(2):89-97. DOI: 10.1016/j.tibs.2005.12.008. View

Wilson V, Smith R, Ma S, Cutler R . Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem. 1987; 262(21):9948-51. View

Kang Y, Koo D, Park J, Choi Y, Lee K, Han Y . Differential inheritance modes of DNA methylation between euchromatic and heterochromatic DNA sequences in ageing fetal bovine fibroblasts. FEBS Lett. 2001; 498(1):1-5. DOI: 10.1016/s0014-5793(01)02472-3. View

Miller C, Sweatt J . Covalent modification of DNA regulates memory formation. Neuron. 2007; 53(6):857-69. DOI: 10.1016/j.neuron.2007.02.022. View

Erickson C, Barnes C . The neurobiology of memory changes in normal aging. Exp Gerontol. 2003; 38(1-2):61-9. DOI: 10.1016/s0531-5565(02)00160-2. View

Suzuki M, Bird A . DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008; 9(6):465-76. DOI: 10.1038/nrg2341. View

Fuke C, Shimabukuro M, Petronis A, Sugimoto J, Oda T, Miura K . Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet. 2004; 68(Pt 3):196-204. DOI: 10.1046/j.1529-8817.2004.00081.x. View

10.

Monsey M, Ota K, Akingbade I, Hong E, Schafe G . Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala. PLoS One. 2011; 6(5):e19958. PMC: 3098856. DOI: 10.1371/journal.pone.0019958. View

11.

Chahrour M, Jung S, Shaw C, Zhou X, Wong S, Qin J . MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008; 320(5880):1224-9. PMC: 2443785. DOI: 10.1126/science.1153252. View

12.

Guo J, Ma D, Mo H, Ball M, Jang M, Bonaguidi M . Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat Neurosci. 2011; 14(10):1345-51. PMC: 3183401. DOI: 10.1038/nn.2900. View

13.

Hardingham G, Chawla S, Johnson C, Bading H . Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature. 1997; 385(6613):260-5. DOI: 10.1038/385260a0. View

14.

Kotini A, Mpakali A, Agalioti T . Dnmt3a1 upregulates transcription of distinct genes and targets chromosomal gene clusters for epigenetic silencing in mouse embryonic stem cells. Mol Cell Biol. 2011; 31(7):1577-92. PMC: 3135298. DOI: 10.1128/MCB.01093-10. View

15.

Klugmann M, Symes C, Leichtlein C, Klaussner B, Dunning J, Fong D . AAV-mediated hippocampal expression of short and long Homer 1 proteins differentially affect cognition and seizure activity in adult rats. Mol Cell Neurosci. 2005; 28(2):347-60. DOI: 10.1016/j.mcn.2004.10.002. View

16.

Bading H, Greenberg M . Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science. 1991; 253(5022):912-4. DOI: 10.1126/science.1715095. View

17.

Feng J, Zhou Y, Campbell S, Le T, Li E, Sweatt J . Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci. 2010; 13(4):423-30. PMC: 3060772. DOI: 10.1038/nn.2514. View

18.

Zhang S, Zou M, Lu L, Lau D, Ditzel D, Delucinge-Vivier C . Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity. PLoS Genet. 2009; 5(8):e1000604. PMC: 2718706. DOI: 10.1371/journal.pgen.1000604. View

19.

SHOLL D . Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat. 1953; 87(4):387-406. PMC: 1244622. View