TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation.
Dynamic changes in 5-methylcytosine (5mC) have been implicated in the regulation of gene expression critical for consolidation of memory. However, little is known about how these changes in 5mC are regulated in the adult brain. The enzyme methylcytosine dioxygenase TET1 (TET1) has been shown to promote active DNA demethylation in the nervous system. Therefore, we took a viral-mediated approach to overexpress the protein in the hippocampus and examine its potential involvement in memory formation. We found that Tet1 is a neuronal activity-regulated gene and that its overexpression leads to global changes in modified cytosine levels. Furthermore, expression of TET1 or a catalytically inactive mutant (TET1m) resulted in the upregulation of several neuronal memory-associated genes and impaired contextual fear memory. In summary, we show that neuronal Tet1 regulates DNA methylation levels and that its expression, independent of its catalytic activity, regulates the expression of CNS activity-dependent genes and memory formation.
Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Garrett A
GA
Kaas
Chun
C
Zhong
Dawn E
DE
Eason
Daniel L
DL
Ross
Raj V
RV
Vachhani
Guo-Li
GL
Ming
Jennifer R
JR
King
Hongjun
H
Song
J David
JD
Sweatt
D000256:Adenoviridae / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002490:Central Nervous System / Q000502:physiology*; D002911:Chrysenes / Q000378:metabolism*; D003214:Conditioning, Classical / Q000502:physiology; D003292:Convulsants / Q000633:toxicity; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005481:Flurothyl / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006900:Hydroxylation / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000235:genetics*; D014161:Transduction, Genetic
D002911:Chrysenes; D003292:Convulsants; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; D011189:Potassium Chloride; D003596:Cytosine; D005481:Flurothyl; D006899:Mixed Function Oxygenases; C008422:5-methylchrysene