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Epigenetic control of female puberty

Nature Neuroscience volume 16, pages 281–289 (2013)Cite this article

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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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Figure 1: In vivo inhibition of DNA methylation results in pubertal failure.
Figure 2: In vivo inhibition of DNA methylation prevents puberty by disrupting developmental events upstream from the GnRH-pituitary-ovarian axis.
Figure 3: The initiation of puberty is accompanied by increased promoter methylation and decreased expression of two PcG genes required for PcG-mediated gene silencing in the MBH.
Figure 4: The Cbx7 and Eed genes are expressed in kisspeptin neurons of the ARC.
Figure 5: Increased Kiss1 expression in the MBH at the initiation of puberty is accompanied by eviction of EED from the Kiss1 promoter and changes in associated repressive and activating histone modifications, without changes in DNA methylation.
Figure 6: EED delivered to the ARC of immature female rats is recruited to the Kiss1 promoter and represses kisspeptin expression.
Figure 7: EED delivered to the ARC of immature female rats inhibits GnRH pulse frequency without changing pulse amplitude.
Figure 8: EED delivered to the ARC of immature female rats delays puberty, disrupts estrous cycle and impairs fertility.

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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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Author notes

  1. Alberto Loche, Gabi Kaidar & J Gabriel Knoll

    Present address: Present addresses: Friedrich Miescher Institute for Biomedical Research Novartis Research Foundation, Basel, Switzerland (A. Loche), Maccabi Health Services, Pardes-Hana, Israel (G.K.) and Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, USA (J.G.K.).,

Authors and Affiliations

  1. Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA

    Alejandro Lomniczi, Alberto Loche, Juan Manuel Castellano, Oline K Ronnekleiv, Gabi Kaidar, J Gabriel Knoll, Hollis Wright & Sergio R Ojeda

  2. Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon, USA

    Oline K Ronnekleiv & Martha Bosch

  3. Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California, USA

    Gerd P Pfeifer

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Contributions

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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Correspondence to Alejandro Lomniczi or Sergio R Ojeda.

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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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