Li, X.Wei, W.Zhao, Q.-Y.Widagdo, J.Baker-Andresen, D.Flavell, C. R.Zhang, YiBredy, T. W.D'Alessio, Ana2014-06-182014Li, X., W. Wei, Q.-Y. Zhao, J. Widagdo, D. Baker-Andresen, C. R. Flavell, A. D’Alessio, Y. Zhang, and T. W. Bredy. 2014. “Neocortical Tet3-Mediated Accumulation of 5-Hydroxymethylcytosine Promotes Rapid Behavioral Adaptation.” Proceedings of the National Academy of Sciences 111 (19) (May 13): 7120–7125.1091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:123324995-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.en-USJournal Article2014-06-1810.1073/pnas.1318906111