The potential contribution of epigenetics to the regulation of puberty has never been addressed. In the present report, we provide evidence that an epigenetic mechanism of transcriptional repression, operating within the neuroendocrine brain, plays a significant role in the timing of female puberty. Our results identify the PcG system of transcriptional silencing 20, 28 as a central element of this repressive mechanism. Hypothalamic expression of Cbx7 and Eed, two PcG genes required for PcG action 29, 32, decreases preceding the onset of puberty, and this change is associated with increased DNA methylation of their 5′-flanking regions. Conversely, pharmacological inhibition of DNA methylation prevented the pubertal increase in Eed and Cbx7 DNA methylation, reversed the low peripubertal Eed and Cbx7 mRNA levels to elevated early juvenile values, and delayed puberty. This delay was not due to a non-specific or toxic effect of the inhibitor, because the animals failed to reach puberty despite exhibiting a body weight much greater than that attained by control rats at puberty. Moreover, it was not caused by changes in the secretion of two different hormones, PRL
