Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair

Research output: Contribution to journalArticle

Huimei Yu, Yijing Su, Jaehoon Shin, Chun Zhong, Junjie U. Guo, Yi Lan Weng, Fuying Gao, Daniel H. Geschwind, Giovanni Coppola, Guo Li Ming, Hongjun Song

Contrary to the long-held belief that DNA methylation of terminally differentiated cells is permanent and essentially immutable, post-mitotic neurons exhibit extensive DNA demethylation. The cellular function of active DNA demethylation in neurons, however, remains largely unknown. Tet family proteins oxidize 5-methylcytosine to initiate active DNA demethylation through the base-excision repair (BER) pathway. We found that synaptic activity bi-directionally regulates neuronal Tet3 expression. Functionally, knockdown of Tet or inhibition of BER in hippocampal neurons elevated excitatory glutamatergic synaptic transmission, whereas overexpressing Tet3 or Tet1 catalytic domain decreased it. Furthermore, dysregulation of Tet3 signaling prevented homeostatic synaptic plasticity. Mechanistically, Tet3 dictated neuronal surface GluR1 levels. RNA-seq analyses further revealed a pivotal role of Tet3 in regulating gene expression in response to global synaptic activity changes. Thus, Tet3 serves as a synaptic activity sensor to epigenetically regulate fundamental properties and meta-plasticity of neurons via active DNA demethylation.

Original languageEnglish (US)
Pages (from-to)836-843
Number of pages8
JournalNature Neuroscience
Volume18
Issue number6
DOIs
StatePublished - Jan 1 2015

PMID: 25915473

Altmetrics

Cite this

Standard

Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. / Yu, Huimei; Su, Yijing; Shin, Jaehoon; Zhong, Chun; Guo, Junjie U.; Weng, Yi Lan; Gao, Fuying; Geschwind, Daniel H.; Coppola, Giovanni; Ming, Guo Li; Song, Hongjun.

In: Nature Neuroscience, Vol. 18, No. 6, 01.01.2015, p. 836-843.

Research output: Contribution to journalArticle

Harvard

Yu, H, Su, Y, Shin, J, Zhong, C, Guo, JU, Weng, YL, Gao, F, Geschwind, DH, Coppola, G, Ming, GL & Song, H 2015, 'Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair' Nature Neuroscience, vol. 18, no. 6, pp. 836-843. https://doi.org/10.1038/nn.4008

APA

Yu, H., Su, Y., Shin, J., Zhong, C., Guo, J. U., Weng, Y. L., ... Song, H. (2015). Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. Nature Neuroscience, 18(6), 836-843. https://doi.org/10.1038/nn.4008

Vancouver

Yu H, Su Y, Shin J, Zhong C, Guo JU, Weng YL et al. Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. Nature Neuroscience. 2015 Jan 1;18(6):836-843. https://doi.org/10.1038/nn.4008

Author

Yu, Huimei ; Su, Yijing ; Shin, Jaehoon ; Zhong, Chun ; Guo, Junjie U. ; Weng, Yi Lan ; Gao, Fuying ; Geschwind, Daniel H. ; Coppola, Giovanni ; Ming, Guo Li ; Song, Hongjun. / Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. In: Nature Neuroscience. 2015 ; Vol. 18, No. 6. pp. 836-843.

BibTeX

@article{8d8b26896c974ebaa2c66a966faa2ddf,
title = "Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair",
abstract = "Contrary to the long-held belief that DNA methylation of terminally differentiated cells is permanent and essentially immutable, post-mitotic neurons exhibit extensive DNA demethylation. The cellular function of active DNA demethylation in neurons, however, remains largely unknown. Tet family proteins oxidize 5-methylcytosine to initiate active DNA demethylation through the base-excision repair (BER) pathway. We found that synaptic activity bi-directionally regulates neuronal Tet3 expression. Functionally, knockdown of Tet or inhibition of BER in hippocampal neurons elevated excitatory glutamatergic synaptic transmission, whereas overexpressing Tet3 or Tet1 catalytic domain decreased it. Furthermore, dysregulation of Tet3 signaling prevented homeostatic synaptic plasticity. Mechanistically, Tet3 dictated neuronal surface GluR1 levels. RNA-seq analyses further revealed a pivotal role of Tet3 in regulating gene expression in response to global synaptic activity changes. Thus, Tet3 serves as a synaptic activity sensor to epigenetically regulate fundamental properties and meta-plasticity of neurons via active DNA demethylation.",
author = "Huimei Yu and Yijing Su and Jaehoon Shin and Chun Zhong and Guo, {Junjie U.} and Weng, {Yi Lan} and Fuying Gao and Geschwind, {Daniel H.} and Giovanni Coppola and Ming, {Guo Li} and Hongjun Song",
year = "2015",
month = "1",
day = "1",
doi = "10.1038/nn.4008",
language = "English (US)",
volume = "18",
pages = "836--843",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "6",

}

RIS

TY - JOUR

T1 - Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair

AU - Yu, Huimei

AU - Su, Yijing

AU - Shin, Jaehoon

AU - Zhong, Chun

AU - Guo, Junjie U.

AU - Weng, Yi Lan

AU - Gao, Fuying

AU - Geschwind, Daniel H.

AU - Coppola, Giovanni

AU - Ming, Guo Li

AU - Song, Hongjun

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Contrary to the long-held belief that DNA methylation of terminally differentiated cells is permanent and essentially immutable, post-mitotic neurons exhibit extensive DNA demethylation. The cellular function of active DNA demethylation in neurons, however, remains largely unknown. Tet family proteins oxidize 5-methylcytosine to initiate active DNA demethylation through the base-excision repair (BER) pathway. We found that synaptic activity bi-directionally regulates neuronal Tet3 expression. Functionally, knockdown of Tet or inhibition of BER in hippocampal neurons elevated excitatory glutamatergic synaptic transmission, whereas overexpressing Tet3 or Tet1 catalytic domain decreased it. Furthermore, dysregulation of Tet3 signaling prevented homeostatic synaptic plasticity. Mechanistically, Tet3 dictated neuronal surface GluR1 levels. RNA-seq analyses further revealed a pivotal role of Tet3 in regulating gene expression in response to global synaptic activity changes. Thus, Tet3 serves as a synaptic activity sensor to epigenetically regulate fundamental properties and meta-plasticity of neurons via active DNA demethylation.

AB - Contrary to the long-held belief that DNA methylation of terminally differentiated cells is permanent and essentially immutable, post-mitotic neurons exhibit extensive DNA demethylation. The cellular function of active DNA demethylation in neurons, however, remains largely unknown. Tet family proteins oxidize 5-methylcytosine to initiate active DNA demethylation through the base-excision repair (BER) pathway. We found that synaptic activity bi-directionally regulates neuronal Tet3 expression. Functionally, knockdown of Tet or inhibition of BER in hippocampal neurons elevated excitatory glutamatergic synaptic transmission, whereas overexpressing Tet3 or Tet1 catalytic domain decreased it. Furthermore, dysregulation of Tet3 signaling prevented homeostatic synaptic plasticity. Mechanistically, Tet3 dictated neuronal surface GluR1 levels. RNA-seq analyses further revealed a pivotal role of Tet3 in regulating gene expression in response to global synaptic activity changes. Thus, Tet3 serves as a synaptic activity sensor to epigenetically regulate fundamental properties and meta-plasticity of neurons via active DNA demethylation.

UR - http://www.scopus.com/inward/record.url?scp=84929959512&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929959512&partnerID=8YFLogxK

U2 - 10.1038/nn.4008

DO - 10.1038/nn.4008

M3 - Article

VL - 18

SP - 836

EP - 843

JO - Nature Neuroscience

T2 - Nature Neuroscience

JF - Nature Neuroscience

SN - 1097-6256

IS - 6

ER -

ID: 41876026