Translational control by cis elements acting in trans

描述（由申请人提供）：基因表达的适当控制是所有细胞功能的基础。对翻译的管制是控制的一种形式。翻译控制因子与mRNA内的顺式作用调控元件结合，并通过多种机制抑制或激活其翻译。翻译控制的破坏可能是非常有害的。例如，脆性X智力低下蛋白的突变，它特异性地与mRNA结合并调节其翻译，对人类具有破坏性的后果。 通常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，这些元素可以反式作用。反式调节很可能取决于两种类型的参与转录本的物理关联：提供调节信息的转录本和接收调节信息的转录本。mRNA在颗粒中的浓度是普遍的。所有mRNA都与信使核糖核蛋白复合物（mRNP）中的蛋白质相关，这些蛋白质通常组装成可以通过光学显微镜观察到的较大颗粒，并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，它们的接近提高了不同转录本之间相互作用的可能性，以及反式调节的可能性。该项目的目标是（一）更好地表征已知的反式调节的例子，（二）以确定哪些形式的翻译控制是易受反式调节，及（三）测试额外的mRNA的反式调节。进展应揭示，如果反式调节是相对常见的，但以前没有检测到，因为通常用于研究翻译控制的方法和试剂的局限性。 这项工作的广泛意义在于，反式调节现象，其中一种mRNA可以影响其他mRNA的活性，有可能解释RNA功能获得性疾病，如强直性肌营养不良，脊髓小脑共济失调8，亨廷顿病样2和脆性X相关震颤共济失调综合征。 公共卫生相关性：基因表达的适当调节对所有细胞的功能至关重要。该项目的目标是更好地表征最近发现的基因调控方面，其中控制其翻译的mRNA内的元件可以反式作用于相同mRNA的其他拷贝。这种反式调节现象有可能解释RNA功能获得性疾病，如强直性肌营养不良、脊髓小脑共济失调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.