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Edited* by James L. McGaugh, University of California, Irvine, CA, and approved March 27, 2014 (received for review October 7, 2013)
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.
5-hydroxymethylcytosine and adaptation
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