Metabolic Control of Puberty: Epigenetic Links

青春期的代谢控制：表观遗传联系

• 批准号: 9477692
• 负责人: Alejandro Lomniczi
• 金额: $ 48.23万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-10 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9477692
• 关键词: Address; Affect; Awareness; Binding Proteins; Biological; Complex; DNA Modification Process; Delayed Puberty; Development; Disease; Distal; Enhancers; Epigenetic Process; Female; GNRH1 gene; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Histone Deacetylase; Histones; Homeostasis; Human; Hypothalamic structure; KISS1 gene; Laboratories; Life; Lifting; Link; Malnutrition; Massive Parallel Sequencing; Metabolic; Metabolic Control; Metabolic stress; Modeling; Molecular; Neurokinin B; Neurons; Neurosecretory Systems; Nutrient; Nutritional; Nutritive Value; Outcome; Play; Polycomb; Pregnancy; Process; Proteins; Puberty; RNA; Rattus; Regulation; Repression; Research Personnel; Rodent; Role; SIRT1 gene; Structure of nucleus infundibularis hypothalami; System; Technology; Testing; Vertebral column; chromatin modification; critical developmental period; energy balance; epigenetic regulation; epigenome; gene repression; genome-wide; histone modification; in vivo; insight; member; mind control; next generation sequencing; novel; nutrition; postnatal; prepuberty; promoter; prototype; pubertal timing; public health relevance; pup; recruit; reproductive; reproductive development; response; sensor

 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.

 描述（由申请人提供）：多年来，人们都知道能量平衡可能会受到“发育规划”关键时期发生的营养挑战的永久影响，这种情况发生在人类妊娠晚期和啮齿类动物产后早期众所周知，这些改变会影响女性神经内分泌的生殖发育；营养供应的增加会提前青春期的到来，而营养缺乏则可能会延迟青春期的发生，这可能是由于相关系统的复杂性和缺乏明确的候选分子所致。链接我们最近发现，女性青春期受到表观遗传机制的调节，该机制涉及解除转录沉默子多梳组（PcG）施加的转录抑制音。并且这种抑制作用于参与 GnRH 分泌刺激控制的下游基因（以 Kiss1 基因为代表）。在确定了其基本组成部分后，我们现在已经揭示了一个调节系统的存在，该系统不仅可以实现长期寻求的将营养与神经内分泌生殖发育联系起来的作用，而且还可以接受实验审查。因此，该提议将检验这一假设。能量平衡发育程序的改变通过调节表观遗传沉默机制影响青春期的时间，表观遗传沉默在青春期前的成熟过程中控制 GnRH 的分泌。为此，将检验以下假设：1)改变出生后早期的营养可用性，通过调节 PcG 复合物对青春期激活 (PA) 基因施加的表观遗传抑制音来影响青春期 2) 额外的 PcG 靶基因可能与青春期时间及其营养调节相关。可以使用 RNA 和 ChIP 大规模并行测序技术通过表观基因组分析来识别这一过程；3) 连接营养与青春期发育的表观遗传联系之一是 SIRT1，根据我们的假设，一种燃料感应分子将起到生物变阻器的作用，以沉默/去抑制 PA 基因，以应对早期营养失衡。我们预计，拟议研究的成功结果将为连接能量稳态的综合机制提供重要见解。我们还预计这些研究将显着增强我们对能量平衡紊乱如何影响青春期时间和进展的理解，并使研究人员和信徒意识到这一点。表观遗传学对这些疾病的贡献。