Allele Interactions that Heritably Alter Transcription

遗传性改变转录的等位基因相互作用

• 批准号: 9982447
• 负责人: Vicki Chandler
• 金额: $ 53.97万
• 依托单位: University of Arizona
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9982447&HistoricalAwards=false
• 关键词: Allele; Interactions; Heritably; Alter; Transcription

Recently, cis-and trans-acting mutations that affect paramutation have been isolated. One of the trans-acting mutants, mop1-1 has been shown to play a central role in paramutation and to also affect transposable element silencing. The proposed studies are: to clone mop1 and determine its role in epigenetic regulation; to isolate more cis-acting mutants and to use the existing and newly isolated mutants to identify the key sequences required for paramutation; to characterize the nature of the cis-acting sequences; and to characterize chromatin structural changes that correlate with paramutation. These experiments should provide tests of the chromatin hypothesis and reveal important information on mechanisms of epigenetic regulation in eukaryotes. Paramutation is an interaction between specific alleles that leads to a mitotically and meiotically heritable change in transcription. Paramutation provides an excellent system for studying heritability of transcription states and allele communication. The stable, heritable inactivation or activation of particular genes is crucial during development of multi-cellular organisms to maintain determined gene expression states. Paramutation is likely to involve epigenetic gene control, defined as a modulation of gene expression achieved by mechanisms superimposed upon that conferred by primary DNA sequence. Recent genetic experiments indicate sequences far upstream are required for paramutation, suggesting long-range communication is occurring between sequences located 50 kbp upstream and the promoter proximal region. Genetic evidence also indicates that the two alleles communicate with each other. Based on studies from other eukaryotic systems, chromatin structure is likely to be involved in intra-and inter-allele communication. Epigenetic control of gene expression is mediated by the chromosomal context of the promoter, by modifications of histones and DNA, long-range interactions between distant chromosomal elements, and sub-nuclear organization. Mammalian X-chromosome inactivation, transgene silencing in plants and animals, transposable element regulation, genome imprinting, silencing of yeast mating-type and telemere-located loci, and position effect variegation in Drosophila are examples with underlying epigenetic bases. Information gained from the molecular genetic dissection of an epigenetic phenomenon such as paramutation in maize should be very applicable to epigenetic gene regulation in many other species that also have large amounts of repetitive DNA and high levels of DNA methylation. An eventual understanding of paramutation should reveal how alleles interact in the nucleus to influence the regulation of each other, how such heritable transcription states are established and how they are maintained through numerous cell divisions and transmitted to the next generation.

最近，影响副突变的顺式和反式作用突变已被分离出来。 反式作用突变体之一，mop 1 -1已被证明在副突变中发挥核心作用，也影响转座因子沉默。 拟议的研究包括：克隆MOP 1并确定其在表观遗传调节中的作用;分离更多的顺式作用突变体并使用现有的和新分离的突变体来鉴定副突变所需的关键序列;表征顺式作用序列的性质;以及表征与副突变相关的染色质结构变化。 这些实验将为染色质假说提供检验，并揭示真核生物表观遗传调控机制的重要信息。异突变是特定等位基因之间的相互作用，导致转录中的有丝分裂和减数分裂可遗传的变化。 Paramutation为研究转录状态和等位基因通讯的遗传性提供了一个很好的系统。 特定基因的稳定的、可遗传的失活或激活在多细胞生物体的发育过程中至关重要，以维持确定的基因表达状态。副突变可能涉及表观遗传基因控制，定义为通过叠加在初级DNA序列赋予的机制上实现的基因表达调节。 最近的遗传实验表明，副突变需要远上游的序列，这表明位于上游50 kbp的序列与启动子近端区域之间正在发生远程通讯。 遗传学证据也表明，这两个等位基因相互沟通。 基于其他真核系统的研究，染色质结构可能参与等位基因内和等位基因间的通讯。 基因表达的表观遗传控制由启动子的染色体背景、组蛋白和DNA的修饰、远距离染色体元件之间的长程相互作用和亚核组织介导。 哺乳动物X染色体失活、植物和动物中的转基因沉默、转座因子调节、基因组印记、酵母交配型和端粒定位基因座的沉默以及果蝇中的位置效应杂色都是潜在的表观遗传基础的例子。 从玉米副突变等表观遗传现象的分子遗传学解剖中获得的信息应该非常适用于许多其他物种的表观遗传基因调控，这些物种也具有大量的重复DNA和高水平的DNA甲基化。 对副突变的最终理解应该揭示等位基因如何在细胞核中相互作用以影响彼此的调节，这种可遗传的转录状态如何建立，以及它们如何通过多次细胞分裂维持并传递给下一代。