Functions of the SAFB family identified by iCLIP

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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.