Tet1 is critical for neuronal activity-regulated gene expression and memory extinction.
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.
The Picower Institute for Learning and Memory, 77 Massachusetts Avenue, Cambridge, MA, 02139.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139.|Howard Hughes Medical Institute, Cambridge, MA.
Andrii
A
Rudenko
Whitehead Institute for Biomedical Research, Cambridge, MA.
Meelad M
MM
Dawlaty
The Picower Institute for Learning and Memory, 77 Massachusetts Avenue, Cambridge, MA, 02139.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139.|Howard Hughes Medical Institute, Cambridge, MA.
Jinsoo
J
Seo
Whitehead Institute for Biomedical Research, Cambridge, MA.|Computational and Systems Biology Program, Cambridge, MA 02142, USA.
Albert W
AW
Cheng
The Picower Institute for Learning and Memory, 77 Massachusetts Avenue, Cambridge, MA, 02139.
Jia
J
Meng
Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Thuc
T
Le
Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Kym F
KF
Faull
Whitehead Institute for Biomedical Research, Cambridge, MA.|Department of Biology Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Rudolf
R
Jaenisch
The Picower Institute for Learning and Memory, 77 Massachusetts Avenue, Cambridge, MA, 02139.|Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139.|Howard Hughes Medical Institute, Cambridge, MA.|Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA.
Li-Huei
LH
Tsai
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000503:physiopathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D003214:Conditioning, Classical / Q000502:physiology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D003863:Depression / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005108:Extinction, Psychological / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008124:Locomotion / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000235:genetics; D008297:Male; D018782:Maze Learning; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000235:genetics; D016704:Synapsins / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D008734:Methoxyhydroxyphenylglycol; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D016704:Synapsins; C533005:Npas4 protein, mouse; C540839:TET1 protein, mouse; C010117:3,4-dihydroxyphenylglycol