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      Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS

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          Abstract

          Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate ubiquitously expressed regulators of RNA processing. To understand the molecular impact of ALS-causing mutations on neuronal development and disease, we analysed transcriptomes during in vitro differentiation of motor neurons (MNs) from human control and patient-specific VCP mutant induced-pluripotent stem cells (iPSCs). We identify increased intron retention (IR) as a dominant feature of the splicing programme during early neural differentiation. Importantly, IR occurs prematurely in VCP mutant cultures compared with control counterparts. These aberrant IR events are also seen in independent RNAseq data sets from SOD1- and FUS-mutant MNs. The most significant IR is seen in the SFPQ transcript. The SFPQ protein binds extensively to its retained intron, exhibits lower nuclear abundance in VCP mutant cultures and is lost from nuclei of MNs in mouse models and human sporadic ALS. Collectively, we demonstrate SFPQ IR and nuclear loss as molecular hallmarks of familial and sporadic ALS.

          Abstract

          Intron retention (IR) can increase protein diversity and function, and yet unregulated IR may be detrimental to cellular health. This study shows that aberrant IR occurs in ALS and finds nuclear loss of an RNA-binding protein called SFPQ as a new molecular hallmark in this devastating condition.

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          Most cited references29

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          HITS-CLIP yields genome-wide insights into brain alternative RNA processing

          Summary Protein-RNA interactions play critical roles in all aspects of gene expression. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova2 revealed extremely reproducible RNA binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3′ UTRs, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.
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            A quantitative atlas of polyadenylation in five mammals

            We developed PolyA-seq, a strand-specific and quantitative method for high-throughput sequencing of 3′ ends of polyadenylated transcripts, and used it to globally map polyadenylation (polyA) sites in 24 matched tissues in human, rhesus, dog, mouse, and rat. We show that PolyA-seq is as accurate as existing RNA sequencing (RNA-seq) approaches for digital gene expression (DGE), enabling simultaneous mapping of polyA sites and quantitative measurement of their usage. In human, we confirmed 158,533 known sites and discovered 280,857 novel sites (FDR < 2.5%). On average 10% of novel human sites were also detected in matched tissues in other species. Most novel sites represent uncharacterized alternative polyA events and extensions of known transcripts in human and mouse, but primarily delineate novel transcripts in the other three species. A total of 69.1% of known human genes that we detected have multiple polyA sites in their 3′UTRs, with 49.3% having three or more. We also detected polyadenylation of noncoding and antisense transcripts, including constitutive and tissue-specific primary microRNAs. The canonical polyA signal was strongly enriched and positionally conserved in all species. In general, usage of polyA sites is more similar within the same tissues across different species than within a species. These quantitative maps of polyA usage in evolutionarily and functionally related samples constitute a resource for understanding the regulatory mechanisms underlying alternative polyadenylation.
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              A highly conserved program of neuronal microexons is misregulated in autistic brains.

              Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide "microexons" display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism.
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                Author and article information

                Contributors
                nicholas.luscombe@crick.ac.uk
                rickie.patani@ucl.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                22 May 2018
                22 May 2018
                2018
                : 9
                : 2010
                Affiliations
                [1 ]ISNI 0000 0004 1795 1830, GRID grid.451388.3, The Francis Crick Institute, ; 1 Midland Road, London, NW1 1AT UK
                [2 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Molecular Neuroscience, , UCL Institute of Neurology, Queen Square, ; London, WC1N 3BG UK
                [3 ]ISNI 0000000121901201, GRID grid.83440.3b, Sobell Department of Motor Neuroscience and Movement Disorders, , UCL Institute of Neurology, Queen Square, ; London, WC1N 3BG UK
                [4 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Neuroinflammation, , UCL Institute of Neurology, Queen Square, ; London, WC1N 1PJ UK
                [5 ]ISNI 0000000121901201, GRID grid.83440.3b, UCL Genetics Institute, , University College London, Gower Street, ; London, WC1E 6BT UK
                [6 ]ISNI 0000 0000 9805 2626, GRID grid.250464.1, Okinawa Institute of Science & Technology Graduate University, ; Okinawa, 904-0495 Japan
                Author information
                http://orcid.org/0000-0001-5730-2112
                http://orcid.org/0000-0001-5293-4778
                Article
                4373
                10.1038/s41467-018-04373-8
                5964114
                29789581
                2340b0b0-7af8-487f-894a-4fce30678560
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 7 September 2017
                : 20 April 2018
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