? DESCRIPTION (provided by applicant): It has been known for years that energy balance can be permanently affected by nutritional challenges taking place during a critical period of developmental programming, which in humans occurs during late gestation and in rodents during early post-natal life. It is also well established that these alterations affect female neuroendocrine reproductive development; increased nutritional availability advances the timing of puberty, and nutritional deficiency delays it. Perhaps due to the complexity of the systems involved and the lack of definitive candidates, neither the molecules linking nutritional programming to pubertal development nor the puberty-related genes they may regulate have been identified. We recently discovered that female puberty is regulated by an epigenetic mechanism that involves lifting of a transcriptional repressive tone exerted by the Polycomb group (PcG) of transcriptional silencers, and that this repression is imposed on downstream genes involved in the stimulatory control of GnRH secretion (epitomized by the Kiss1 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 scrutiny. Accordingly, this proposal will test the hypothesis that alterations in the developmental programming 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, the following hypotheses will be tested: 1) That 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. 2) That 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; and 3) That one of the epigenetic link connecting nutrition to pubertal development is SIRT1, a fuel-sensing molecule that according to our hypothesis would function as a biological rheostat to silence/derepress PA genes in response to early nutritional unbalance. We 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. We also anticipate that these studies will significantly enhance our understanding of 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.
|Effective start/end date||7/10/15 → 4/30/20|
- National Institutes of Health: $578,190.00
- National Institutes of Health: $572,406.00