Functions of the SAFB family identified by iCLIP

DNA基因可以翻译成一个或多个信使rna (mRNA)， mRNA反过来表达一种独特的蛋白质。人类基因组中编码的基因总数与低等物种（如小鼠）中的基因数量相似。然而，控制人类基因表达的过程比低等物种要复杂得多，而且单个基因会产生更多的mrna（因此也会产生蛋白质）。这种表达的复杂性在神经元细胞中尤为明显，而控制这一过程的蛋白质功能的改变可能是人类神经系统疾病的基础。我们发现一种以前不知道在神经细胞中表达的蛋白（SAFB1）参与调节特定rna的加工。此外，我们已经鉴定出一种与SAFB1具有非常相似特性的新蛋白，并将其称为saf样调节剂（SLTM）。为了确定这些蛋白质与哪些RNA分子相互作用，我们建议使用一种称为个体核苷酸分辨率交联和免疫沉淀（iCLIP）的强大技术。该技术允许：(i)以高度定量的方式鉴定由SAFB1和SLTM结合的RNA分子；（ii）它们编码的待识别基因和蛋白质。在确定这些mRNA之后，我们将详细分析SAFB1和SLTM如何控制这些mRNA及其编码的蛋白质的表达。使用这种iCLIP技术的初步研究表明，SAFB1控制特定和重要神经系统基因的表达水平。重要的是，它也被证明影响RNA的水平，这种RNA在细胞中形成一个组装点，用于控制RNA加工的许多蛋白质。这项研究将确定SAFB1和SLTM如何影响控制神经元重要过程的基因表达，例如记忆形成。许多已经确定的神经元（SAFB调节）基因与复杂的人类神经系统疾病有关，因此我们的研究结果将对导致人类神经系统疾病的机制产生有价值的新见解。

DNA genes can be translated into one or more messenger RNAs (mRNA) which in turn express a unique protein. The total number of genes encoded in the human genome is similar in number to those found in lower species (e.g. mouse). However, the processes governing gene expression in humans are far more complex than that found in lower species and many more mRNAs (and therefore proteins) are produced from a single gene. This complexity of expression is particularly evident in neuronal cells and the altered functioning of the proteins that govern this process may underlie human neurological diseases. We have found that a protein (SAFB1) not previously known to be expressed in neuronal cells is involved in regulating the processing of specific RNAs. Furthermore, we have identified a novel protein with very similar properties to SAFB1 and called it SAF-like modulator (SLTM). To identify what RNA molecules these proteins interact with we are proposing to use a powerful technique called individual-nucleotide resolution cross-linking and immunoprecipitation (iCLIP). This technique allows: (i) the RNA molecules being bound by SAFB1 and SLTM to be identified in a highly quantitative manner; (ii) the genes and proteins they encode to be identified. Following the identification of these mRNAs we will analyse in detail how SAFB1 and SLTM govern the expression of these mRNA and the proteins they encode. Preliminary studies using this iCLIP technique have shown that SAFB1 governs the levels of expression of specific and important neurological genes. Importantly, it was also shown to influence the levels of an RNA that forms an assembly point in the cell for many of the proteins that govern RNA processing. This investigation will identify how SAFB1 and SLTM influence the expression of genes that governs important processes in neurons, e.g. memory formation. Many of the neuronal (SAFB regulated) genes already identified are associated with complex human neurological conditions and the results of our study will therefore yield valuable and novel insights into mechanisms that cause human neurological diseases.