Tet1 oxidase regulates neuronal gene transcription, active DNA hydroxymethylation, object location memory, and threat recognition memory

Kumar, Dinesh Babu Uthaya; Aggarwal, Milan; Kaas, Garrett A.; Lewis, John W.; Wang, Jing; Ross, Daniel L.; Zhong, Chun; Kennedy, Andrew; Song, Hongjun; Sweatt, J. David

doi:10.1016/j.nepig.2015.10.002

Cited by 44 publications

(41 citation statements)

References 59 publications

(107 reference statements)

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“…This result suggests that Dnmt3 expression might be regulated by varying DNA methylation levels at its promoter (Biergans et al, 2015). The data presented here, however, does not conclusively prove such an auto-regulatory mechanism; but this possibility is certainly worth considering, especially as a similar relationship has also been found recently in mammals (Kumar et al, 2015): In trained Tet1 knock-out mice -with reduced 5hmC and mostly unchanged 5mC levels -genes belonging to active demethylation pathways were upregulated.…”

Section: Temporal Aspects Of Epigenetic Regulation Of Stimulus-specifmentioning

confidence: 39%

“…Interestingly in the Tet1 KO other genes associated with active demethylation (e.g. Gadd45a) were upregulated, suggesting a potential feedback mechanism (Kumar et al, 2015).…”

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

“…reward) conditioning (Day et al, 2013). These studies investigated a range of different brain areas such as the hippocampus (Levenson et al, 2006;Miller and Sweatt, 2007;Miller et al, 2008;Lubin et al, 2008;Hutnick et al, 2009;Sultan et al, 2012;Mizuno et al, 2012;Rudenko et al, 2013;Kaas et al, 2013;Morris et al, 2014), the amygdala (Maddox and Schafe, 2011;Sultan et al, 2012;Monsey et al, 2011;Morris et al, 2014;Kumar et al, 2015) and the cortex (Hutnick et al, 2009;Miller et al, 2010;Sui et al, 2012;Rudenko et al, 2013). In most cases long-term memory formation after aversive and appetitive conditioning was impaired if Dnmts were pharmacologically inhibited or knocked out (Levenson et al, 2006;Miller and Sweatt, 2007;Miller et al, 2008;Lubin et al, 2008;Hutnick et al, 2009;Miller et al, 2010;Feng et al, 2010;Maddox and Schafe, 2011;Monsey et al, 2011;Sui et al, 2012;Oliveira et al, 2012;Day et al, 2013;Morris et al, 2014).…”

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

“…Studies focussing on demethylation -specifically Tet and Gadd45b -however make the picture more complex: a Tet1 KO enhances LTM retention after aversive conditioning and spatial memory tasks, DNA methylation and memory formation in bees whereas the results for contextual fear conditioning disagreed between studies (Rudenko et al, 2013;Kumar et al, 2015). Interestingly in the Tet1 KO other genes associated with active demethylation (e.g.…”

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

“…Evidence presented in this thesis supports the idea that DNA demethylation is involved in the regulation of honey bee memory formation. Several studies in mammals already established a role of Tet and Gadd45b in aversive memory formation (Sultan et al, 2012;Rudenko et al, 2013;Kaas et al, 2013;Kumar et al, 2015). I investigated only Tet expression and 5-hydroxymethylcytosine after olfactory reward conditioning in this thesis and it remains unclear which aspects of memory formation are affected by Tet-mediated demethytlation.…”

Section: Limitations and Future Researchmentioning

confidence: 99%

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DNA methylation and the regulation of stimulus-specific memory formation

Biergans¹

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Memory formation is a crucial task of the brain. It allows animals to dynamically respond to a changing environment by combining information about current and previous experiences. Thus, it promotes complex behaviours such as living in social groups and elaborate foraging tactics. The ability to form memories is present across the animal kingdom in a variety of forms. The honeybee -an eusocial insect -is capable of both 'simple' associative and complex rule learning. Despite decades of research into the mechanisms of memory formation, however, much remains unknown.One little-understood aspect is the regulation of molecular mechanisms during memory formation.Understanding regulation of transcription is particularly important in this context, as transcription is a requirement for any stable memory. Epigenetic mechanisms regulate transcription by directly interacting with chromatin. Importantly, epigenetic mechanisms are conserved across species as distinct as humans and honeybees. This thesis aims to investigate one particular epigenetic mechanism -DNA methylation -and its role in honey bee memory formation by using behavioural, physiological and molecular assays.First, I studied the role of DNA methyltransferases (Dnmts), which catalyse DNA methylation, after olfactory reward learning. Bees were trained to associate an odour with a sugar reward. Dnmts were then blocked after conditioning using a pharmacological inhibitor. 24 hours later, bees were tested for memory retention and generalisation. Dnmt inhibition increased the generalisation to an odour that was not present during the training, thus impairing stimulus-specific memory. This effect was learning-dependent, as bees' response to odours or sugar water alone did not change after treatment. Furthermore, this effect was robust against alterations in the training paradigm, but the directionality depended on the number of training trials. Next, I used Ca2+ -imaging of the bees' primary olfactory centre (i.e. antennal lobe, AL) to investigate whether Dnmts affect changes in AL processing established during memory formation. The AL is involved in odour discrimination and olfactory learning; both processes are also crucial for stimulus-specific memory formation. If Dnmts were inhibited after olfactory reward learning, the AL response to a new odour changed 48 hours later. This effect potentially serves as a functional explanation for the behavioural phenotype observed after Dnmt inhibition. Furthermore, this study provides the first in vivo evidence for Dnmt-mediated regulation of neuronal networks during memory formation.As DNA methylation regulates transcription, I next investigated the effect of Dnmt inhibition on gene expression. Using qPCR I studied 30 memory-associated genes. In response to Dnmt inhibition, 9 genes were upregulated after conditioning. For some of these genes I then investigated their i methylation patterns using a bisulfite conversion based Mass spectrometry approach. Memory formation changed the methylation pattern compared to both...

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Section: Temporal Aspects Of Epigenetic Regulation Of Stimulus-specifmentioning

confidence: 39%

“…Interestingly in the Tet1 KO other genes associated with active demethylation (e.g. Gadd45a) were upregulated, suggesting a potential feedback mechanism (Kumar et al, 2015).…”

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

Section: Limitations and Future Researchmentioning

confidence: 99%

See 3 more Smart Citations

DNA methylation and the regulation of stimulus-specific memory formation

Biergans¹

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Regulation of 5-Hydroxymethylcytosine Distribution by the TET Enzymes

2019

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Ten-Eleven Translocation 1 and 2 Confer Overlapping Transcriptional Programs for the Proliferation of Cultured Adult Neural Stem Cells

Shimozaki

2016

Cell Mol Neurobiol

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Adult neurogenesis originates from neural stem cells (NSCs) in specific regions of the adult brain. The molecular mechanisms that control the self-renewal and multipotency of NSCs have not been fully elucidated. In recent years, emerging evidence has revealed that ten-eleven translocation (TET) family DNA dioxygenases TET1 and TET2 play important roles in the central nervous system. Here, I present evidence that Tet1 and Tet2 are expressed in cultured NSCs derived from adult mouse brain and play an important role in the proliferative self-renewal of NSCs in an undifferentiated state. The investigation of intracellular molecular networks involving both Tet1 and Tet2 by gene knockdown and comprehensive genetic analyses showed that overlapping molecular mechanisms involving TET1 and TET2 regulate the expression of at least 16 genes required for DNA replication and cell cycle control. Interestingly, transcriptional regulation of the selected gene through TET1 and TET2 did not correlate with direct CpG demethylation of the gene promoter. These findings suggest that TET1 and TET2 play an important role in the proliferation of NSCs in the adult mouse brain by specifically regulating common genes for DNA replication and the cell cycle.

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Tet1 oxidase regulates neuronal gene transcription, active DNA hydroxymethylation, object location memory, and threat recognition memory

Cited by 44 publications

References 59 publications

DNA methylation and the regulation of stimulus-specific memory formation

DNA methylation and the regulation of stimulus-specific memory formation

Regulation of 5-Hydroxymethylcytosine Distribution by the TET Enzymes

Ten-Eleven Translocation 1 and 2 Confer Overlapping Transcriptional Programs for the Proliferation of Cultured Adult Neural Stem Cells

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