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FUS‐mediated regulation of alternative RNA processing in neurons: insights from global transcriptome analysis

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Fused in sarcoma (FUS) is an RNA‐binding protein that is causally associated with oncogenesis and neurodegeneration. Recently, the role of FUS in neurodegeneration has been extensively studied, because mutations in FUS are associated with amyotrophic lateral sclerosis (ALS), and the FUS protein has been identified as a major component of intracellular inclusions in neurodegenerative disorders including ALS and frontotemporal lobar degeneration. FUS is a key molecule in transcriptional regulation and RNA processing including processes such as pre‐messenger RNA (mRNA) splicing and polyadenylation. Interaction of FUS with various components of the transcription machinery, spliceosome, and the 3′‐end processing machinery has been identified. Furthermore, recent advances in high‐throughput transcriptomic profiling approaches have enabled us to determine the mechanisms of FUS‐dependent RNA processing networks at a cellular level. These analyses have revealed that depletion of FUS in neuronal cells affects alternative splicing and alternative polyadenylation of thousands of mRNAs. Gene ontology analysis has suggested that FUS‐modulated genes are implicated in neuronal functions and development. CLIP‐seq of FUS has shown that FUS is frequently clustered around these alternative sites of nascent RNA. ChIP‐seq of RNA polymerase II (RNAP II) has demonstrated that an interaction between FUS and nascent RNA downregulates local transcriptional activity of RNAP II, which is critically involved in RNA processing. Both alternative splicing and alternative polyadenylation are fundamental processes by which cells expand their transcriptomic diversity, and are particularly essential in the nervous system. Dependence of transcriptomic diversity on FUS makes the nervous system vulnerable to neurodegeneration, when FUS is functionally compromised. WIREs RNA 2016, 7:330–340. doi: 10.1002/wrna.1338 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > Splicing Regulation/Alternative Splicing RNA Processing > 3' End Processing
Transcriptome analysis by high‐throughput sequencing. (a) CLIP‐seq produces a transcriptome‐wide map of in vivo RNA‐binding sites of a specific RNA‐binding protein. RNA‐seq is a high‐throughput sequencing method employed for genome‐wide transcriptome profiling, which has the potential to elucidate the number, structure, and abundance of transcript by sequencing randomly fragmented RNA or cDNA. CAGE‐seq is a high‐throughput, tag‐based sequencing method designed to scrutinize the 5′ end of capped cDNAs. PolyA‐seq is a high‐throughput sequencing method for the detection and quantification of the 3′ ends of polyadenylated transcripts. (b) Nascent‐Seq (genome‐wide sequencing of nascent RNA) is a high‐throughput sequencing method to identify chromatin‐bound nascent RNA obtained from the lysis of cells and washing of cell nuclei with NUN buffer consisting of high concentrations of NaCl, urea, and NP‐40. This sequencing method detects nascent RNA molecules attached to elongating RNAP II. RNAP II ChIP‐seq shows genome‐wide distribution of RNAP II, which reflects the transcriptional status of RNAP II. Accumulation of RNAP II ChIP‐tags is observed at the sites where RNAP II pauses.
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FUS‐dependent regulation of alternative cleavage and polyadenylation. FUS is recruited to RNA immediately after its transcription and locally inhibits RNAP II transcription. When FUS binds immediately downstream of PAS (step A, gray triangle), FUS promotes binding of CPSF160 to PAS‐containing RNA (step B, gray triangle), which leads to cleavage and polyadenylation of the bound RNA. When FUS binds upstream of the PAS of an APA site or a PAS is not present, only the transcription suppressive effect of FUS is observed and the FUS‐bound transcript is downregulated. Through such regulation, FUS globally controls APA events, which are implicated in neuronal activities and synaptic transmission in neurons.
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FUS‐dependent regulation of alternative splicing. FUS regulates alternative splicing through direct interaction with spliceosome components, such as U1 snRNP, as well as through suppression of local transcriptional activity of RNAP II. FUS‐dependent alternative splicing events are implicated in neuronal functions including synaptogenesis, axonogenesis, and neuronal development.
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FUS‐dependent regulation of transcriptional activity of RNAP II. FUS interacts with the nascent RNA soon after its transcription, which stimulates formation of a fibrous assembly. Then, the FUS assembly binds to CTD, attenuates its serine‐2 phosphorylation, and induces local stalling of RNAP II.
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RNA Processing > 3′ End Processing
RNA Processing > Splicing Regulation/Alternative Splicing
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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