Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation.
5-hydroxymethylcytosine (5-hmC) is a novel DNA modification that is highly enriched in the adult brain and dynamically regulated by neural activity. 5-hmC accumulates across the lifespan; however, the functional relevance of this change in 5-hmC and whether it is necessary for behavioral adaptation have not been fully elucidated. Moreover, although the ten-eleven translocation (Tet) family of enzymes is known to be essential for converting methylated DNA to 5-hmC, the role of individual Tet proteins in the adult cortex remains unclear. Using 5-hmC capture together with high-throughput DNA sequencing on individual mice, we show that fear extinction, an important form of reversal learning, leads to a dramatic genome-wide redistribution of 5-hmC within the infralimbic prefrontal cortex. Moreover, extinction learning-induced Tet3-mediated accumulation of 5-hmC is associated with the establishment of epigenetic states that promote gene expression and rapid behavioral adaptation.
Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
Xiang
X
Li
Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
Wei
W
Wei
Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
Qiong-Yi
QY
Zhao
Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
Jocelyn
J
Widagdo
Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
Danay
D
Baker-Andresen
Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
Charlotte R
CR
Flavell
Whitehead Institute for Biomedical Research, Cambridge, MA, 02142;
Ana
A
D'Alessio
Harvard Medical School, Boston, MA, 02115; and.
Yi
Y
Zhang
Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, CA, 92617 t.bredy@uq.edu.au.
Timothy W
TW
Bredy
D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003213:Conditioning, Psychological / Q000502:physiology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D049308:Dioxygenases; D044127:Epigenesis, Genetic / Q000502:physiology; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology*; D055106:Genome-Wide Association Study; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019579:Neocortex / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C551915:Tet3 protein, mouse