Abstract
The timing of puberty is controlled by many genes. The elements coordinating this process have not, however, been identified. Here we show that an epigenetic mechanism of transcriptional repression times the initiation of female puberty in rats. We identify silencers of the Polycomb group (PcG) as principal contributors to this mechanism and show that PcG proteins repress Kiss1, a puberty-activating gene. Hypothalamic expression of two key PcG genes, Eed and Cbx7, decreased and methylation of their promoters increased before puberty. Inhibiting DNA methylation blocked both events and resulted in pubertal failure. The pubertal increase in Kiss1 expression was accompanied by EED loss from the Kiss1 promoter and enrichment of histone H3 modifications associated with gene activation. Preventing the eviction of EED from the Kiss1 promoter disrupted pulsatile gonadotropin-releasing hormone release, delayed puberty and compromised fecundity. Our results identify epigenetic silencing as a mechanism underlying the neuroendocrine control of female puberty.
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Acknowledgements
We thank M.E. Costa for technical assistance with the in situ hybridization procedures and the preparation of ovaries for morphological observation. This work was supported by US National Institute of Health (NIH; HD025123-ARRA and 8P51OD011092) and US National Science Foundation (IOS1121691) grants to S.R.O. and by NIH grants NS43330 and DK68098 to O.K.R., and by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (FP7-PEOPLE-2010-IOF) to J.M.C.
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A. Lomniczi and S.R.O. designed the project and wrote the paper. A. Lomniczi was involved in all aspects of the study. S.R.O. coordinated the project and performed the intrahypothalamic injections of viruses, including the imaging studies. A. Loche and J.M.C. ran global methylation arrays, ChIP and targeted methylation assays. O.K.R. and M.B. performed the single cell PCR experiments. G.K. measured mRNA by qPCR. J.G.K. determined the number of kisspeptin neurons in the ARC. H.W. designed the Perl script for the detection of HOTAIR consensus motifs and analyzed the data from DNA methylation arrays. G.P.P. advised us on methylation assays.
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Lomniczi, A., Loche, A., Castellano, J. et al. Epigenetic control of female puberty. Nat Neurosci 16, 281–289 (2013). https://doi.org/10.1038/nn.3319
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DOI: https://doi.org/10.1038/nn.3319
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