Institute for Mind and Biology and Department of Psychology, University of Chicago, Chicago, IL 60637.
Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16651-6. doi: 10.1073/pnas.1310643110. Epub 2013 Sep 25.
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.
在季节性繁殖的脊椎动物中，通过甲状腺激素依赖的机制，光照时长的变化会诱发完全不同的行为和生殖表型。冬季的光照时长会抑制生殖神经内分泌功能，但这种抑制作用不会持续超过 6 个月，从而确保春季的生殖功能恢复。这种基因组的可塑性表明，表观遗传在季节性生殖表型的建立中发挥了作用。在这里，我们报告说，仓鼠下丘脑中 III 型脱碘酶（dio3）基因近端启动子的 DNA 甲基化是可逆的，对于光周期时间的测量至关重要。短光照和类似冬季的褪黑素抑制了下丘脑 DNA 甲基转移酶的表达，降低了 dio3 启动子的 DNA 甲基化，从而上调了 dio3 的表达并诱导了性腺退化。过度甲基化减弱了对短光照的生殖反应。春季对短光照的迟钝性重新建立了 dio3 启动子、dio3 表达和生殖能力的类似夏季的甲基化，揭示了哺乳动物大脑中 DNA 甲基化的动态和可逆机制，在生理时间定向中发挥了核心作用。
