Metabolic Control of Puberty: Epigenetic Links

青春期的代谢控制：表观遗传联系

• 批准号: 8940852
• 负责人: Alejandro Lomniczi
• 金额: $ 57.82万
• 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/8940852
• 关键词: Address; Affect; Biological; Complex; DNA Modification Process; Delayed Puberty; Development; Disease; Distal; Enhancers; Epigenetic Process; Female; Gene Silencing; Gene Targeting; Genes; Histones; Homeostasis; Human; Hypothalamic structure; 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; Protein Binding; Proteins; Puberty; RNA; Rattus; Regulation; Repression; Research Personnel; Rodent; Role; Structure of nucleus infundibularis hypothalami; System; Technology; Testing; Time; Vertebral column; base; chromatin modification; critical developmental period; energy balance; epigenetic regulation; epigenome; gene repression; genome-wide; histone modification; in vivo; insight; kisspeptin; member; mind control; next generation sequencing; novel; nutrition; postnatal; prepuberty; programs; promoter; prototype; pubertal timing; public health relevance; pup; 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（由申请方提供）：多年来，人们已经知道，在“发育编程”的关键时期发生的营养挑战可能会永久影响能量平衡，这在人类中发生在妊娠晚期，在啮齿动物中发生在出生后早期。众所周知，这些变化会影响女性神经内分泌生殖发育;营养供应增加会提前青春期的时间，而营养缺乏会推迟青春期的时间。也许由于所涉及的系统的复杂性以及缺乏确定的候选物，将营养程序与青春期发育联系起来的分子以及它们可能调节的青春期相关基因都尚未被确定。我们最近发现，女性青春期是由一种表观遗传机制调节的，该机制涉及解除转录沉默子Polycomb组（PcG）施加的转录抑制基调，并且这种抑制作用被施加到参与GnRH分泌的刺激控制的下游基因上通过发现一种控制青春期时间的新的表观遗传机制并确定其基本组成部分，我们现在已经揭示了一个调节系统的存在，它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的审查。因此，本提案将检验这一假设，即能量平衡的发育程序的改变通过调节表观遗传沉默机制来影响青春期的时间，表观遗传沉默机制在青春期前成熟期间保持GnRH分泌。为此，将测试以下假设：1）在出生后早期改变营养供应影响青春期，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音调。2)利用RNA和ChIP大规模平行测序技术，通过表观基因组范围的分析，可以鉴定出与青春期时间和该过程的营养调节潜在相关的其他PcG靶基因;和3）SIRT 1是连接营养与青春期发育的表观遗传联系之一，根据我们的假设，这种燃料传感分子将作为生物变阻器来沉默/抑制PA基因以响应早期营养失衡。我们预计，一个成功的结果，拟议的研究将提供重要的见解，整合机制连接能量稳态，神经内分泌大脑和青春期的控制。我们还预计，这些研究将显著提高我们对能量平衡障碍如何影响青春期时间和进展的理解，并使研究人员和临床医生意识到表观遗传学对这些疾病的贡献。