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Tet1 is critical for neuronal activity-regulated gene expression and memory extinction.

ABSTRACT: The ten-eleven translocation (Tet) family of methylcytosine dioxygenases catalyze oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promote DNA demethylation. Despite the abundance of 5hmC and Tet proteins in the brain, little is known about the functions of the neuronal Tet enzymes. Here, we analyzed Tet1 knockout mice (Tet1KO) and found downregulation of multiple neuronal activity-regulated genes, including Npas4, c-Fos, and Arc. Furthermore, Tet1KO animals exhibited abnormal hippocampal long-term depression and impaired memory extinction. Analysis of the key regulatory gene, Npas4, indicated that its promoter region, containing multiple CpG dinucleotides, is hypermethylated in both naive Tet1KO mice and after extinction training. Such hypermethylation may account for the diminished expression of Npas4 itself and its downstream targets, impairing transcriptional programs underlying cognitive processes. In summary, we show that neuronal Tet1 regulates normal DNA methylation levels, expression of activity-regulated genes, synaptic plasticity, and memory extinction.

SUBMITTER: Rudenko A

PROVIDER: S-EPMC4543319 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Tet1 is critical for neuronal activity-regulated gene expression and memory extinction.

Rudenko Andrii A Dawlaty Meelad M MM Seo Jinsoo J Cheng Albert W AW Meng Jia J Le Thuc T Faull Kym F KF Jaenisch Rudolf R Tsai Li-Huei LH

Neuron 20130901 6

The ten-eleven translocation (Tet) family of methylcytosine dioxygenases catalyze oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promote DNA demethylation. Despite the abundance of 5hmC and Tet proteins in the brain, little is known about the functions of the neuronal Tet enzymes. Here, we analyzed Tet1 knockout mice (Tet1KO) and found downregulation of multiple neuronal activity-regulated genes, including Npas4, c-Fos, and Arc. Furthermore, Tet1KO animals exhibited ab ...[more]

PMID: 24050401

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Project description:The dynamic regulation of DNA methylation in postmitotic neurons is necessary for memory formation and other adaptive behaviors. Ten-eleven translocation 1 (TET1) plays a part in these processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby initiating active DNA demethylation. However, attempts to pinpoint its exact role in the nervous system have been hindered by contradictory findings, perhaps due in part, to a recent discovery that two isoforms of the Tet1 gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript (Tet1S ) encoding an N-terminally truncated TET1 protein and a full-length Tet1 (Tet1FL ) transcript encoding canonical TET1 are co-expressed in the adult mouse brain. We show that Tet1S is the predominantly expressed isoform and is highly enriched in neurons, whereas Tet1FL is generally expressed at lower levels and more abundant in glia, suggesting their roles are at least partially cell type-specific. Using viral-mediated, isoform and neuron-specific molecular tools, we find that the individual repression of each transcript leads to the dysregulation of unique gene ensembles and contrasting changes in basal synaptic transmission. In addition, Tet1S repression enhances, while Tet1FL impairs, hippocampal-dependent memory in male mice. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the mammalian brain.SIGNIFICANCE STATEMENT In the brain, activity-dependent changes in gene expression are required for the formation of long-term memories. DNA methylation plays an essential role in orchestrating these learning-induced transcriptional programs by influencing chromatin accessibility and transcription factor binding. Once thought of as a stable epigenetic mark, DNA methylation is now known to be impermanent and dynamically regulated, driving neuroplasticity in the brain. We found that Tet1, a member of the ten-eleven translocation (TET) family of enzymes that mediates removal of DNA methyl marks, is expressed as two separate isoforms in the adult mouse brain and that each differentially regulates gene expression, synaptic transmission and memory formation. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the CNS.

Project description:Backgroundp23 belongs to the highly conserved p24 family of type I transmembrane proteins, which participate in the bidirectional protein transport between the endoplasmic reticulum and Golgi apparatus. Mammalian p23 has been shown to interact with ?-secretase complex, and modulate secretory trafficking as well as intramembranous processing of amyloid precursor protein in cultured cells. Negative modulation of ?-amyloid production by p23 in cultured cell lines suggested that elevation of p23 expression in neurons might mitigate cerebral amyloid burden.ResultsWe generated several lines of transgenic mice expressing human p23 in neurons under the control of Thy-1.2 promoter. We found that even a 50% increase in p23 levels in the central nervous system of mice causes post-natal growth retardation, severe neurological problems characterized by tremors, seizure, ataxia, and uncoordinated movements, and premature death. The severity of the phenotype closely correlated with the level of p23 overexpression in multiple transgenic lines. While the number and general morphology of neurons in Hup23 mice appeared to be normal throughout the brain, abnormal non-Golgi p23 localization was observed in a subset of neurons with high transgene expression in brainstem. Moreover, detailed immunofluorescence analysis revealed marked proliferation of astrocytes, activation of microglia, and thinning of myelinated bundles in brainstem of Hup23 mice.ConclusionsThese results demonstrate that proper level of p23 expression is critical for neuronal function, and perturbing p23 function by overexpression initiates a cascade of cellular reactions in brainstem that leads to severe motor deficits and other neurological problems, which culminate in premature death. The neurological phenotype observed in Hup23 mice highlights significant adverse effects associated with manipulating neuronal expression of p23, a previously described negative modulator of ?-secretase activity and ?-amyloid production. Moreover, our report has broader relevance to molecular mechanisms in several neurodegenerative diseases as it highlights the inherent vulnerability of the early secretory pathway mechanisms that ensure proteostasis in neurons.

Dataset Information

Tet1 is critical for neuronal activity-regulated gene expression and memory extinction.

Publications

Tet1 is critical for neuronal activity-regulated gene expression and memory extinction.

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