Allele Interactions that Heritably Alter Transcription

最近，影响参数转换的顺式和反式作用突变已经被分离出来。作为反式作用突变体之一，MOP1-1已被证明在参数突变中发挥核心作用，并影响转座元件沉默。建议的研究包括：克隆MOP1并确定其在表观遗传调控中的作用；分离更多的顺式作用突变体，并利用现有的和新分离的突变体来鉴定顺式作用所需的关键序列；表征顺式作用序列的性质；以及表征与顺式作用相关的染色质结构变化。这些实验应该提供染色质假说的检验，并揭示真核生物表观遗传调控机制的重要信息。参数突变是特定等位基因之间的相互作用，导致转录中有丝分裂和减数分裂可遗传的变化。参数突变为研究转录状态的遗传力和等位基因交流提供了一个很好的系统。在多细胞生物体的发育过程中，特定基因的稳定、可遗传的失活或激活是维持确定的基因表达状态的关键。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序列所赋予的机制上实现的对基因表达的调节。最近的遗传学实验表明，远上游的序列是进行参数突变所必需的，这表明位于上游50kbp的序列和启动子近端区域之间存在着远程通信。遗传证据还表明，这两个等位基因相互交流。根据其他真核生物系统的研究，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是由启动子的染色体环境、组蛋白和DNA的修饰、远端染色体元件之间的远程相互作用和亚核组织所介导的。哺乳动物的X染色体失活、动植物中的转基因沉默、转座元件调节、基因组印记、酵母交配型和端粒定位位点的沉默以及果蝇中的位置效应变异都是有潜在表观遗传学基础的例子。从玉米等表观遗传现象的分子遗传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重复的DNA和高水平的DNA甲基化。对参数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是如何建立的，以及它们是如何通过大量的细胞分裂保持并传递给下一代的。

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.