Translational control by cis elements acting in trans

描述(申请人提供)：基因表达的适当控制是所有细胞功能的基础。对翻译的管制是一种控制形式。翻译控制因子与mRNAs中的顺式作用调控元件结合，并通过各种机制抑制或激活其翻译。翻译控制的中断可能会造成非常严重的破坏。例如，脆性X智力低下蛋白的突变对人类造成了毁灭性的后果。脆性X智力低下蛋白与mRNAs特异结合，并调节其翻译。人们普遍认为，顺式作用的翻译调控元件只能作用于它所在的信使核糖核酸。然而，我们最近发现这些元件可以在反式作用中发挥作用。反式转录的调控很可能取决于两种参与转录的物理联系：提供调控信息的转录和接收调控信息的转录。MRNAs在颗粒中的浓度很高。所有的mRNAs都与信使核糖核蛋白复合体(MRNPs)中的蛋白质相关，mRNPs通常被组装成更大的颗粒，可以用光学显微镜观察到，并有可能产生高局部浓度的mRNAs。这些mRNAs存在于一个共享的微环境中，它们的接近增加了不同转录本之间相互作用的可能性，以及反式调控的可能性。该项目的目标是(I)更好地描述已知的反式调控的例子，(Ii)确定哪些形式的翻译调控容易受到反式调控的影响，以及(Iii)测试额外的反式调控的mRNAs。进展应该揭示反式调控是否相对常见，但由于通常用于研究翻译控制的方法和试剂的局限性，以前没有被检测到。这项工作的广泛意义在于，反式调节现象，其中一个mRNA可以影响其他mRNAs的活性，有可能解释RNA功能增强疾病，如强直性肌营养不良，脊髓小脑性共济失调8，亨廷顿病样2和脆性X相关震颤共济综合征。 公共卫生相关性：对基因表达的适当调控对所有细胞的功能至关重要。这个项目的目标是更好地描述最近发现的基因调控的一个方面，即mRNAs中控制其翻译的元件可以反式作用于同一mRNAs的其他拷贝。这种反式调节现象有可能解释RNA功能增强疾病，如强直性肌营养不良、脊髓小脑性共济失调8、亨廷顿病样2和脆性X相关震颤共济失调综合征。

DESCRIPTION (provided by applicant): Proper control of gene expression underlies the function of all cells. Regulation of translation is one form of control. Translational control factors bind to cis-acting regulatory elements within mRNAs and, by a variety of mechanisms, repress or activate their translation. Disruption of translational control can be very damaging. For example, mutation of the Fragile X mental retardation protein, which binds specifically to mRNAs and regulates their translation, has devastating consequences in humans. It is generally accepted that a cis-acting translational control element can act only on the mRNA in which it resides. However, we recently found that these elements can act in trans. Regulation in trans very likely depends on physical association of the two types of participating transcripts: those that provide regulatory information, and those that receive regulatory information. Concentration of mRNAs in particles is widespread. All mRNAs are associated with proteins in messenger ribonucleoprotein complexes (mRNPs), which are often assembled into larger particles that can be visualized by light microscopy and have the potential to create a high local concentration of mRNAs. These mRNAs exist in a shared microenvironment, and their proximity raises the possibility of interactions between different transcripts, and the potential for trans regulation. The goals of this project are (i) to better characterize the known example of trans regulation, (ii) to determine which forms of translational control are susceptible to regulation in trans, and (iii) to test additional mRNAs for regulation in trans. Progress should reveal if trans regulation is relatively common but not previously detected because of limitations of the methods and reagents commonly used to study translational control. The broad significance of this work is that the phenomenon of trans regulation, in which one mRNA can influence the activity of other mRNAs, has the potential to explain RNA gain-of-function diseases such as myotonic dystrophy, spinocerebellar ataxia 8, Huntington's disease-like 2 and fragile X-associated tremor ataxia syndrome. PUBLIC HEALTH RELEVANCE: Proper regulation of gene expression is critical for the function of all cells. The goal of this project is to better characterize a recently discovered aspect of gene regulation in which elements within mRNAs that control their translation can act in trans on other copies of the same mRNA. This phenomenon of trans regulation has the potential to explain RNA gain-of-function diseases such as myotonic dystrophy, spinocerebellar ataxia 8, Huntington's disease-like 2 and fragile X-associated tremor ataxia syndrome.