Metabolic Control of Puberty via Epigenetics

通过表观遗传学控制青春期的代谢

• 批准号: 9044344
• 负责人: Carlos Alejandro Toro
• 金额: $ 5.8万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9044344
• 关键词: Address; Affect; Binding Proteins; Complex; DNA Modification Process; Delayed Puberty; Development; Disease; Distal; Enhancers; Epigenetic Process; Female; Gene Silencing; Gene Targeting; Genes; Histones; Homeostasis; Human; Hypothalamic structure; KISS1 gene; Laboratories; Life; Lifting; Link; Malnutrition; Massive Parallel Sequencing; Metabolic Control; Metabolic stress; Modeling; Molecular; National Research Service Awards; Neurokinin B; Neurons; Neurosecretory Systems; Nutrient; Nutritional; Nutritive Value; Outcome; Polycomb; Pregnancy; Process; Proteins; Puberty; RNA; Rattus; Regulation; Repression; Research Personnel; Rodent; Role; Structure of nucleus infundibularis hypothalami; System; Technology; Testing; Time; Vertebral column; base; critical developmental period; energy balance; epigenetic regulation; epigenome; experimental analysis; gene repression; genome-wide; histone modification; in vivo; insight; mind control; next generation sequencing; novel; nutrition; postnatal; prepuberty; programs; promoter; prototype; pubertal timing; public health relevance; pup; reproductive; reproductive development

 DESCRIPTION (provided by applicant): 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.

 描述（由申请方提供）：许多研究已经证明，在发育规划的关键时期发生的营养变化可能会对能量平衡产生不利影响，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。这些改变已被证明严重影响女性神经内分泌生殖发育。营养过剩会使青春期提前;营养不足会使青春期推迟。可能是由于所涉及的系统的复杂性和缺乏精确的候选者，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控的青春期相关基因都没有被确定。最近在我们实验室进行的研究表明，女性青春期是由表观遗传机制，转录抑制，涉及Polycomb组（PcG）的转录沉默。我们的研究表明，这种抑制作用施加在涉及GnRH分泌的刺激控制的下游基因上（以Kiss基因为代表）。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种调节系统的存在，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，而且还可以进行实验分析。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分泌受到抑制。为此，将检验两个主要假设：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;和2）可能与青春期的时间和该过程的营养调节相关的额外的PcG靶基因可以通过使用RNA和ChIP的表观基因组分析来鉴定。大规模平行测序技术。我预计，一个成功的结果，拟议的研究将提供重大的见解，整合机制连接能量稳态，神经内分泌大脑和青春期的控制。我还预见，这些研究将大大有助于我们了解能量平衡障碍如何影响青春期的时间和进展，并将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。