EPIGENETIC REGULATION TISSUE-SPECIFIC GENE TRANSCRIPTION

表观遗传调控组织特异性基因转录

基本信息

批准号：
7544993
负责人：
Alexandra Christin Racanelli
金额：
$ 3.91万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2011-05-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7544993
关键词：
A Mouse Address Adult Behavior Binding Binding Proteins Blood Cells Bone Marrow Cells Class Commit Complex DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA Modification Process Deposition Development Embryo Embryonic Development Epigenetic Process Event Fetal Liver Fibroblasts Folylpolyglutamate synthase Gene Expression Genes Genetic Genetic Transcription Genome Glutamate-Ammonia Ligase Hematopoiesis Hepatocyte Human Human Biology Indium Kidney Knock-out Knockout Mice Laboratories Link Liver Measures Mediating Memory Molecular Mouse Strains Mus Normal tissue morphology Numbers Partial Hepatectomy Pathology Pathway interactions Pattern Pliability Process Production Protein Isoforms Proteins RNA Polymerase II Regulation Role Series Specificity Staging Stem cells Testing Thinking Tissue-Specific Gene Expression Tissues Trans-Activators Transcript cell type clinically relevant grasp histone-binding proteins homologous recombination interest methyl group mouse genome precursor cell programs promoter research study senescence transcription factor trend

项目摘要

DESCRIPTION (provided by applicant): Hematopoiesis involves an intricate pattern of gene expression that is programmed in early precursor cells to fully differentiated cell types, and the whole pathway represents an intricate example of tissue specific gene expression. The tissue specificity of mammalian gene expression is determined by the levels of trans-acting factors, as well as by epigenetic events that allow both the long-term control and the flexibility required by development. The complexity of mammalian gene expression is realized from the limited number (ca 28,000) of genes in human and mouse genomes by a series of mechanisms that often results in the production of several transcripts from a single gene under tight control in different stages of differentiation. We have been studying the mouse folylpolyglutamate synthetase (fpgs) gene as an example of a genetic locus in which two distinct gene products are produced from two distantly placed promoters in a tissue-specific pattern. This gene is particularly interesting because any given tissue produces transcript from only one promoter, although tissues that express from the one or the other or neither are known. Our studies on the mouse fpgs gene have indicated that there are layers of coordinated control of the two promoters, but that events at the two promoters follow very different patterns. My initial studies have recently shown that this gene constitutes one of the very few known examples of transcriptional interference in an endogenous gene, and also one of the few promoters for which tissue-specific silencing correlates with DNA methylation at a CpG-sparse promoter in normal tissues. These studies have also raised the fundamentally important point that transcriptional initiation complexes are poised over at least some promoters both in tissues that produce a mature transcript and in those which do not produce detectable transcript. The focus of this proposal is to explore how DNA methylation and transcriptional interference contribute to promoter choice at the mouse fpgs gene in a tissue-specific fashion, and to determine whether and the extent to which the phenomena we see integrating control at this single two promoter gene capture general trends in control of gene expression across the mouse genome. A central aspect of human biology is the programming of information present in a single fertilized cell that encodes what proteins are expressed in every cell in the adult human being. Such a tissue-specific expression pattern is seen nowhere as clearly as in the development of the blood cells. In this application, I propose to study how modification of DNA and of a class of DMA-bound proteins (histones) directs this tissue specific information flow and memory.

描述（由申请人提供）：造血涉及一种复杂的基因表达模式，该模式在早期的前体细胞中编程为完全分化的细胞类型，整个途径代表了组织特异性基因表达的复杂例子。哺乳动物基因表达的组织特异性取决于跨作用因子的水平，以及允许长期控制和发育所需的灵活性的表观遗传事件。哺乳动物基因表达的复杂性是通过一系列机制在人和小鼠基因组中的有限数量（Ca 28,000）实现的，这些机制通常会导致在不同阶段在不同阶段的紧密控制下从单个基因产生几个转录本。我们一直在研究小鼠Folylypolyglutamate合成酶（FPGS）基因，作为遗传基因座的一个例子，其中两个不同的基因产物是由两个远处放置的启动子以组织特异性模式产生的。该基因特别有趣，因为任何给定的组织都会仅从一个启动子产生转录本，尽管从一个或另一个或两者都不知道的组织。我们对小鼠FPGS基因的研究表明，两个启动子的协调控制层，但是两个启动子的事件遵循截然不同的模式。我的最初研究最近表明，该基因构成了内源基因中转录干扰的少数已知实例之一，也是少数几个启动子之一，在正常情况下，在正常情况下，组织特异性的沉默与DNA甲基化与DNA甲基化相关。组织。这些研究还提出了从根本上重要的观点，即在产生成熟的转录物以及未产生可检测转录本的组织中，至少某些启动子在组织中的转录起始复合物具有依据。该提案的重点是探索DNA甲基化和转录干扰如何以组织特异性的方式在小鼠FPGS基因上有助于启动子选择，并确定我们在这个单个两个启动子处是否在该现象中看到的现象是否在多大程度上基因捕获了整个小鼠基因组基因表达控制的一般趋势。人类生物学的一个核心方面是单个受精细胞中存在的信息编程，该信息编码了成年人的每个细胞中蛋白质所表达的内容。这种组织特异性的表达模式被没有像血细胞的发育一样清楚地看到。在此应用中，我建议研究DNA和一类DMA结合蛋白（组蛋白）的修饰如何指导该组织特定的信息流和记忆。