Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair.
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.
1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Huimei
H
Yu
1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Yijing
Y
Su
1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jaehoon
J
Shin
1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Chun
C
Zhong
1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Junjie U
0000000188710055
JU
Guo
1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Yi-Lan
YL
Weng
1] Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2] Program in Neurogenetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [3] Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [4] Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Fuying
F
Gao
1] Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2] Program in Neurogenetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [3] Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [4] Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Daniel H
DH
Geschwind
1] Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2] Program in Neurogenetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [3] Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [4] Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Giovanni
0000000321051061
G
Coppola
1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [4] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [5] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Guo-li
GL
Ming
1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [4] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Hongjun
H
Song
D000818:Animals; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D049308:Dioxygenases; D055785:Gene Knockdown Techniques; D006706:Homeostasis / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*
D004247:DNA; D004268:DNA-Binding Proteins; D049308:Dioxygenases; D011518:Proto-Oncogene Proteins; D018091:Receptors, AMPA; C551915:Tet3 protein, mouse