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      Epigenetic Control of Female Puberty

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          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 major 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, decreases and methylation of their promoters increases preceding puberty. Inhibiting DNA methylation blocks both events and results in pubertal failure. The pubertal increase in Kiss1 is 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 disrupts pulsatile GnRH release, delays puberty, and compromises fecundity. Our results identify epigenetic silencing as a novel mechanism underlying the neuroendocrine control of female puberty.

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          Most cited references 47

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          Mechanisms of polycomb gene silencing: knowns and unknowns.

          Polycomb proteins form chromatin-modifying complexes that implement transcriptional silencing in higher eukaryotes. Hundreds of genes are silenced by Polycomb proteins, including dozens of genes that encode crucial developmental regulators in organisms ranging from plants to humans. Two main families of complexes, called Polycomb repressive complex 1 (PRC1) and PRC2, are targeted to repressed regions. Recent studies have advanced our understanding of these complexes, including their potential mechanisms of gene silencing, the roles of chromatin modifications, their means of delivery to target genes and the functional distinctions among variant complexes. Emerging concepts include the existence of a Polycomb barrier to transcription elongation and the involvement of non-coding RNAs in the targeting of Polycomb complexes. These findings have an impact on the epigenetic programming of gene expression in many biological systems.
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            Multivalent engagement of chromatin modifications by linked binding modules.

            Various chemical modifications on histones and regions of associated DNA play crucial roles in genome management by binding specific factors that, in turn, serve to alter the structural properties of chromatin. These so-called effector proteins have typically been studied with the biochemist's paring knife--the capacity to recognize specific chromatin modifications has been mapped to an increasing number of domains that frequently appear in the nuclear subset of the proteome, often present in large, multisubunit complexes that bristle with modification-dependent binding potential. We propose that multivalent interactions on a single histone tail and beyond may have a significant, if not dominant, role in chromatin transactions.
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              Polycomb silencing mechanisms and the management of genomic programmes.

              Polycomb group complexes, which are known to regulate homeotic genes, have now been found to control hundreds of other genes in mammals and insects. First believed to progressively assemble and package chromatin, they are now thought to be localized, but induce a methylation mark on histone H3 over a broad chromatin domain. Recent progress has changed our view of how these complexes are recruited, and how they affect chromatin and repress gene activity. Polycomb complexes function as global enforcers of epigenetically repressed states, balanced by an antagonistic state that is mediated by Trithorax. These epigenetic states must be reprogrammed when cells become committed to differentiation.

                Author and article information

                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                11 January 2013
                27 January 2013
                March 2013
                01 September 2013
                : 16
                : 3
                : 281-289
                [1 ]Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA
                [2 ]Department of Physiology and Pharmacology, Oregon Health Science University, Portland, Oregon, USA
                [3 ]Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California, USA
                Author notes
                Correspondence should be addressed to A. Lomniczi ( lomniczi@ 123456ohsu.edu ) or S.R. Ojeda ( ojedas@ 123456ohsu.edu )

                A. Loche’s present address: Friedrich Miescher Institute for Biomedical Research Novartis, Research Foundation, 4058 Basel, Switzerland.

                G. Kaidar’s present address: Maccabi Health Services, Pardes-Hana, Israel.

                J.G. Knoll’s present address: Department of Pediatrics, Oregon Health Science University, ortland, Oregon USA


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                Funded by: National Institute of Child Health & Human Development : NICHD
                Award ID: R01 HD025123 || HD



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