A number of studies have documented that energy balance can be enduringly affected by nutritional changes taking place during the essential period of developmental programming, which in humans occurs during late gestation and in rodents during the course of their early post-natal life. These alterations have been shown to severely affect female neuroendocrine reproductive development. An excess of nutrients availability advances the timing of puberty; nutritional deficiency delays it. Possibly due to the complexity of the systems involved and absence of precise candidates, neither the molecules linking nutritional programming to pubertal development nor the puberty-related genes they may regulate have been identified. Recently studies performed in our laboratory have demonstrated that female puberty is regulated by an epigenetic mechanism, of transcriptional repression that involves the Polycomb group (PcG) of transcriptional silencers. Our studies showed that this repression is imposed on downstream genes implicated in the stimulatory control of GnRH secretion (epitomized by Kiss gene). By discovering a novel epigenetic mechanism controlling the timing of puberty and identifying its basic components, we have now unveiled the existence of a regulatory system that may not only fulfill the long-sought out role of linking nutrition to neuroendocrine reproductive development, but is also amenable to experimental analysis. Accordingly, this proposal will test the hypothesis that alterations in the developmental programing of energy balance affect the timing of puberty by regulating the mechanism of epigenetic silencing that keeps GnRH secretion in check during prepubertal maturation. To this end, two main hypotheses will be tested: 1) Altering nutrient availability during early postnatal life affects puberty by regulating an epigenetic repressive tone imposed by the PcG complex on puberty-activating (PA) genes; and 2) Additional PcG target genes potentially relevant to the timing of puberty and to the nutritional regulation of this process can be identified by epigenome-wide anlaysis using RNA-and ChIP- massively parallel sequencing technology. I anticipate that a successful outcome of the proposed studies will provide major insights into the integrative mechanisms linking energy homeostasis, the neuroendocrine brain and the control of puberty. I also foresee that these studies will substantially contribute to our understanding on how disorders in energy balance influence the timing and progression of puberty, and will make researchers and clinicians aware of the epigenetics contribution to these disorders.
The studies proposed in this NRSA application will allow the applicant to test the hypothesis that altering the developmental programming of energy balance by changing nutrient availability during early postnatal life affects the timing of female puberty y modifying an epigenetic mechanism of transcriptional repression controlling GnRH secretion. We anticipate that these studies will significantly enhance our understanding of how early-life metabolic stress affects female reproductive maturation.
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