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Research Article

Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

Xiang Li, Wei Wei, Qiong-Yi Zhao, Jocelyn Widagdo, Danay Baker-Andresen, Charlotte R. Flavell, Ana D’Alessio, Yi Zhang, and Timothy W. Bredy
PNAS first published April 22, 2014; https://doi.org/10.1073/pnas.1318906111
Xiang Li
aQueensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
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Wei Wei
aQueensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
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Qiong-Yi Zhao
aQueensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
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Jocelyn Widagdo
aQueensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
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Danay Baker-Andresen
aQueensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
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Charlotte R. Flavell
aQueensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
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Ana D’Alessio
bWhitehead Institute for Biomedical Research, Cambridge, MA, 02142;
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Yi Zhang
cHarvard Medical School, Boston, MA, 02115; and
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Timothy W. Bredy
aQueensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
dCenter for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, CA, 92617
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  • For correspondence: t.bredy@uq.edu.au
  1. Edited* by James L. McGaugh, University of California, Irvine, CA, and approved March 27, 2014 (received for review October 7, 2013)

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Significance

We have discovered a critical role for ten-eleven translocation 3-mediated hydroxylation of 5-methycytosine in the adult prefrontal cortex in mediating rapid behavioral adaptation. 5-hydroxymethylcytosine (5-hmC) is highly dynamic in response to fear extinction training, and rather than simply reflecting a functional intermediary of active DNA demethylation, the learning-induced intergenic accumulation of 5-hmC creates an epigenetic state that promotes experience-dependent gene expression and behavioral adaptation.

Abstract

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.

Footnotes

  • ↵1X.L., W.W., and Q.-Y.Z. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. E-mail: t.bredy{at}uq.edu.au.
  • Author contributions: X.L., W.W., Q.-Y.Z., and T.W.B. designed research; X.L., W.W., J.W., D.B.-A., and C.R.F. performed research; Q.-Y.Z., J.W., A.D., and Y.Z. contributed new reagents/analytic tools; X.L., W.W., Q.-Y.Z., and T.W.B. analyzed data; and X.L., W.W., and T.W.B. wrote the paper.

  • The authors declare no conflict of interest.

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1318906111/-/DCSupplemental.

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5-hydroxymethylcytosine and adaptation
Xiang Li, Wei Wei, Qiong-Yi Zhao, Jocelyn Widagdo, Danay Baker-Andresen, Charlotte R. Flavell, Ana D’Alessio, Yi Zhang, Timothy W. Bredy
Proceedings of the National Academy of Sciences Apr 2014, 201318906; DOI: 10.1073/pnas.1318906111

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5-hydroxymethylcytosine and adaptation
Xiang Li, Wei Wei, Qiong-Yi Zhao, Jocelyn Widagdo, Danay Baker-Andresen, Charlotte R. Flavell, Ana D’Alessio, Yi Zhang, Timothy W. Bredy
Proceedings of the National Academy of Sciences Apr 2014, 201318906; DOI: 10.1073/pnas.1318906111
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