Metabolic Control of Puberty: Epigenetic Links

 描述(由申请人提供)：多年来，人们已经知道，在“发育规划”的关键时期发生的营养挑战可能会永久性地影响能量平衡，人类的营养挑战发生在妊娠晚期，啮齿动物的营养挑战发生在出生后早期。众所周知，这些变化会影响女性的神经内分泌生殖发育；营养供应的增加会提前青春期的时间，而营养不足则会推迟青春期。也许由于涉及的系统的复杂性和缺乏确定的候选者，既没有发现将营养编程与青春期发育联系起来的分子，也没有发现它们可能调节的青春期相关基因。我们最近发现，女性青春期受一种表观遗传机制的调节，该机制涉及解除转录沉默蛋白聚梳(Polycomb group，PcG)施加的转录抑制基调，并且这种抑制作用施加于参与刺激控制GnRH分泌的下游基因(以Kiss1基因为代表)。通过发现一种控制青春期时机的新的表观遗传学机制并确定其基本成分，我们现在揭示了一种调控系统的存在，该系统不仅可以完成人们长期寻求的将营养与神经内分泌生殖发育联系起来的角色，而且还可以进行实验研究。因此，这项提议将通过调节表观遗传沉默的机制来检验这一假说，即能量平衡的发育编程的变化通过调节表观遗传沉默的机制来控制青春期前GnRH的分泌。为此，将检验以下假设：1)出生后早期改变营养物质的可获得性通过调节PcG复合体对青春期激活(PA)基因施加的表观遗传抑制基调来影响青春期。2)通过使用RNA和芯片大规模并行测序技术进行表观基因组分析，可以确定与青春期时机和这一过程的营养调控潜在相关的其他PcG靶基因；以及3)将营养与青春期发育联系起来的表观遗传学联系之一是SIRT1，根据我们的假设，它将作为生物变阻器发挥作用，沉默/降低PA基因，以响应早期的营养失衡。我们预计，拟议研究的成功结果将为能量平衡、神经内分泌脑和青春期控制的综合机制提供重要的见解。我们还预计，这些研究将显著增强我们对能量平衡障碍如何影响青春期时间和进程的理解，并将使研究人员和临床医生意识到表观遗传学对这些障碍的贡献。

 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.