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Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved September 5, 2013 (received for review June 5, 2013)
Significance
This work examined whether epigenetic mechanisms participate in the regulation of seasonal reproduction. In long-day (summer) breeding hamsters, exposure to inhibitory winter photoperiods, or winter-like patterns of melatonin, altered DNA methyltransferase expression; decreased DNA methylation in the proximal promoter region of deiodinase type III (dio3) in the hypothalamus; and, in turn, increased hypothalamic dio3 expression. Pharmacological blockade of photoperiod-driven demethylation attenuated reproductive responses to winter photoperiods. Winter demethylation was reversed in anticipation of spring: spontaneous reproductive development was accompanied by remethylation of the dio3 promoter and decreases in dio3 mRNA. Methylation dynamics in the adult brain are reversible and may constitute an important component of the mechanism by which seasonal time is represented in the nervous system.
Abstract
In seasonally breeding vertebrates, changes in day length induce categorically distinct behavioral and reproductive phenotypes via thyroid hormone-dependent mechanisms. Winter photoperiods inhibit reproductive neuroendocrine function but cannot sustain this inhibition beyond 6 mo, ensuring vernal reproductive recrudescence. This genomic plasticity suggests a role for epigenetics in the establishment of seasonal reproductive phenotypes. Here, we report that DNA methylation of the proximal promoter for the type III deiodinase (dio3) gene in the hamster hypothalamus is reversible and critical for photoperiodic time measurement. Short photoperiods and winter-like melatonin inhibited hypothalamic DNA methyltransferase expression and reduced dio3 promoter DNA methylation, which up-regulated dio3 expression and induced gonadal regression. Hypermethylation attenuated reproductive responses to short photoperiods. Vernal refractoriness to short photoperiods reestablished summer-like methylation of the dio3 promoter, dio3 expression, and reproductive competence, revealing a dynamic and reversible mechanism of DNA methylation in the mammalian brain that plays a central role in physiological orientation in time.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: tyler.stevenson{at}abdn.ac.uk.
Author contributions: T.J.S. and B.J.P. designed research; T.J.S. performed research; T.J.S. and B.J.P. analyzed data; and T.J.S. and B.J.P. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. KC153107–KC153111, EU812319, and EU812320).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1310643110/-/DCSupplemental.
Role of methylation in seasonal rhythms
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- Physiology
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