Regulated Retrotransposon Elements in Neuroendocrine System

神经内分泌系统中调控的逆转录转座子元件

• 批准号: 7670220
• 负责人: Janusz Adam Puc
• 金额: $ 10.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670220
• 关键词: Address; Biochemical; Biological; Biological Models; Biology; Boundary Elements; Cell Lineage; Cell Nucleus; Cells; Chromatin; Chromatin Modeling; Chromosome Structures; Chromosomes; Complex; Data; Development; Disease; Distal; Elements; Endocrine; Epigenetic Process; Event; Family; Feedback; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Silencing; Gene Targeting; Genes; Genetic; Genetic Materials; Genetic Transcription; Genome; Gland; Growth; Higher Order Chromatin Structure; Histones; Homeostasis; Hormones; Hypothalamic structure; Indium; Individual; Insulator Elements; Lactation; Lead; Lysine; Maintenance; Memory; Metabolism; Methylation; Modification; Molecular; Mono-S; Mus; N-terminal; Neuraxis; Neurosecretory Systems; Nuclear; Nucleic Acid Regulatory Sequences; Organ; Peripheral; Pituitary Gland; Positioning Attribute; Process; Proteins; Regulation; Regulator Genes; Reproduction; Retrotransposon; Rice; Role; SET Domain; SETDB1 gene; Scaffolding Protein; Shapes; Short Interspersed Nucleotide Elements; Signal Transduction; Somatotropin; Specific qualifier value; Study models; Time; Transcriptional Activation; Transferase; Transgenic Mice; Vertebrates; cell type; chromatin modification; chromatin remodeling; histone modification; human disease; in vivo; interest; member; novel; pituitary gland development; precursor cell; programs; promoter

DESCRIPTION (provided by applicant): A central question in biology and development is to delineate the sequence of epigenetic and nucleo-architectural events by which transcription units "switch" from silenced to active, relocating from heterochromatic to euchromatic regions. The pituitary gland is a critical component of the neuroendocrine system present in all vertebrates, and is essential in the maintenance of homeostasis, metabolism, reproduction, growth, and lactation. Under the integrated control of central nervous system signals from the hypothalamus and feedback signals from peripheral organs, the pituitary gland synthesizes and secretes trophic hormones from distinct endocrine cell types. Although key regulators involved in the specification of pituitary cell lineages are now well defined, the mechanisms underlying the spatial and temporal order of molecular events by which genes silenced in precursor cells are ultimately activated in the mature gland, leading to precise, cell-restricted regulation of gene expression are still to be unveiled In this regard, the GH gene, while initially silenced, is then activated in a common precursor for somatotropes and lactotropes, but becomes actively repressed in lactotropes. Yet, the precise molecular mechanisms controlling GH expression remain vague. Preliminary data indicates that an insulator element exists within a distal regulatory region of the mouse growth hormone gene locus that may act to establish independent domains of differential chromatin modifications. Interestingly, the identified putative insulator element belongs to the family of SINE retrotransposons, which have been shown to have a profound role in shaping eukaryotic genomes and are recognized as a causal agent for human disease. I propose to investigate: 1) whether this putative insulator element functions in pituitary development and, if so, to determine the molecular mechanism of its action, and 2) whether a specific member of the SET domain family of histone methyl transferases, ESET, provides the key molecular mechanism underlying the shift of nuclear compartments of the GH gene regulatory promoter. These two specific aims will be addressed in vivo: transgenic mice will be generated and analyzed to evaluate the role of this retrotransposon and the ESET protein in the control of the GH gene expression. Deeper understanding of the processes regulating the timing of relocation and ultimate gene expression in the model system of the developing pituitary gland, may not only lead to general principles in gene activation, but also to the development of new therapies for growth-related diseases.

描述（由申请人提供）： 生物学和发育中的一个中心问题是描述表观遗传和核结构事件的序列，通过这些事件，转录单位从沉默“切换”到活跃，从异染色质区重新定位到常染色质区。 脑下垂体是所有脊椎动物神经内分泌系统的重要组成部分，在维持体内平衡、新陈代谢、生殖、生长和哺乳中至关重要。在来自下丘脑的中枢神经系统信号和来自外周器官的反馈信号的综合控制下，垂体合成并分泌来自不同内分泌细胞类型的营养激素。虽然参与垂体细胞谱系特化的关键调控因子现在已经被很好地定义，但是在前体细胞中沉默的基因最终在成熟腺体中被激活的分子事件的空间和时间顺序的潜在机制，导致精确的、细胞限制的基因表达调控，仍然有待揭示 在这方面，GH基因，而最初沉默，然后激活一个共同的前体促生长素和催乳素，但成为积极抑制催乳素。然而，控制GH表达的精确分子机制仍然模糊。初步数据表明，绝缘子元件存在于小鼠生长激素基因座的远端调控区域内，该基因座可用于建立差异染色质修饰的独立结构域。有趣的是，所鉴定的推定绝缘子元件属于SINE反转录转座子家族，其已被证明在形成真核基因组中具有深远的作用，并被认为是人类疾病的致病因子。我提议调查：1）是否这种假定的绝缘子元件在垂体发育中起作用，如果是的话，确定其作用的分子机制，和2）是否组蛋白甲基转移酶的SET结构域家族的特定成员ESET提供了GH基因调节启动子的核隔室移位的关键分子机制。这两个具体的目标将在体内解决：转基因小鼠将产生和分析，以评估这种逆转录转座子和ESET蛋白在控制GH基因表达的作用。 更深入地了解过程调节搬迁的时间和最终的基因表达的模型系统中的发育垂体，不仅可能导致基因激活的一般原则，而且还发展新的治疗生长相关疾病。