Translational control by cis elements acting in trans

描述（由申请人提供）：适当控制基因表达是所有细胞功能的基础。翻译规范是一种控制形式。翻译控制因子与mrna内的顺式调控元件结合，并通过多种机制抑制或激活mrna的翻译。平移控制的中断可能是非常有害的。例如，脆性X智力迟钝蛋白的突变对人类具有毁灭性的后果。脆性X智力迟钝蛋白专门与mrna结合并调节其翻译。人们普遍认为，顺式作用的翻译控制元件只能作用于其所在的mRNA。然而，我们最近发现这些元素可以在反式中起作用。翻译中的监管很可能取决于两种参与转录本的物理关联：提供监管信息的转录本和接受监管信息的转录本。mrna在颗粒中的浓度是普遍存在的。所有mrna都与信使核糖核蛋白复合物（mRNPs）中的蛋白质相关，mRNPs通常被组装成更大的颗粒，可以通过光学显微镜看到，并且有可能产生高局部浓度的mrna。这些mrna存在于一个共享的微环境中，它们的接近性提高了不同转录本之间相互作用的可能性，以及反式调控的潜力。该项目的目标是：(i)更好地表征已知的反式调控的例子，（ii）确定哪些形式的翻译控制易受反式调控的影响，以及（iii）测试反式调控的其他mrna。进展应该揭示反式调控是否相对普遍，但由于研究翻译控制的常用方法和试剂的局限性，以前没有检测到。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mRNA的活性，有可能解释RNA功能获得性疾病，如肌强直性营养不良、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.