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      Splicing in immune cells—mechanistic insights and emerging topics

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          Abstract

          Splicing mechanisms—relevance for immune cells

          Abstract

          Differential splicing of mRNAs not only enables regulation of gene expression levels, but also ensures a high degree of gene-product diversity. The extent to which splicing of mRNAs is utilized as a mechanism in immune cells has become evident within the last few years. Still, only a few of these mechanisms have been well studied. In this review, we discuss some of the best-understood mechanisms, for instance the differential splicing of CD45 in T cells, as well as immunoglobulin genes in B cells. Beyond that we provide general mechanistic insights on how, when and where this process takes place and discuss the current knowledge regarding these topics in immune cells. We also highlight some of the reported links to immune-related diseases, genome-wide sequencing studies that revealed thousands of differentially spliced transcripts, as well as splicing studies on immune cells that remain mechanistically not fully understood. We thereby display potential emerging topics for future studies centered on splicing mechanisms in immune cells.

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          Most cited references76

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          Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells

          Recent molecular studies have revealed that, even when derived from a seemingly homogenous population, individual cells can exhibit substantial differences in gene expression, protein levels, and phenotypic output 1–5 , with important functional consequences 4,5 . Existing studies of cellular heterogeneity, however, have typically measured only a few pre-selected RNAs 1,2 or proteins 5,6 simultaneously because genomic profiling methods 3 could not be applied to single cells until very recently 7–10 . Here, we use single-cell RNA-Seq to investigate heterogeneity in the response of bone marrow derived dendritic cells (BMDCs) to lipopolysaccharide (LPS). We find extensive, and previously unobserved, bimodal variation in mRNA abundance and splicing patterns, which we validate by RNA-fluorescence in situ hybridization (RNA-FISH) for select transcripts. In particular, hundreds of key immune genes are bimodally expressed across cells, surprisingly even for genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrate previously unobserved levels of heterogeneity between cells. Some of the observed bimodality can be attributed to closely related, yet distinct, known maturity states of BMDCs; other portions reflect differences in the usage of key regulatory circuits. For example, we identify a module of 137 highly variable, yet co-regulated, antiviral response genes. Using cells from knockout mice, we show that variability in this module may be propagated through an interferon feedback circuit involving the transcriptional regulators Stat2 and Irf7. Our study demonstrates the power and promise of single-cell genomics in uncovering functional diversity between cells and in deciphering cell states and circuits.
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            A genomic view of alternative splicing.

            Recent genome-wide analyses of alternative splicing indicate that 40-60% of human genes have alternative splice forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Here we review these recent results from bioinformatics studies, assess their reliability and consider the impact of alternative splicing on biological functions. Although the 'big picture' of alternative splicing that is emerging from genomics is exciting, there are many challenges. High-throughput experimental verification of alternative splice forms, functional characterization, and regulation of alternative splicing are key directions for research. We recommend a community-based effort to discover and characterize alternative splice forms comprehensively throughout the human genome.
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              RECURRENT MUTATIONS IN THE U2AF1 SPLICING FACTOR IN MYELODYSPLASTIC SYNDROMES

              Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole genome sequencing to perform an unbiased comprehensive screen to discover all the somatic mutations in a sAML sample and genotyped these loci in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (S34) in U2AF1 was recurrently mutated in 13/150 (8.7%) de novo MDS patients, with suggestive evidence of an associated increased risk of progression to sAML. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3′ end of introns and mutations are located in highly conserved zinc fingers in U2AF1 1,2 . Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This novel, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.
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                Author and article information

                Journal
                Int Immunol
                Int. Immunol
                intimm
                International Immunology
                Oxford University Press (UK )
                0953-8178
                1460-2377
                April 2017
                08 June 2017
                08 June 2017
                : 29
                : 4 , Special Issue: Dynamics of RNA Regulation in the Immune System
                : 173-181
                Affiliations
                [1 ] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Center for Diabetes Research (DZD) , 85764 München-Neuherberg, Germany
                Author notes
                Correspondence to: E. Glasmacher; E-mail: elke.glasmacher@ 123456helmholtz-muenchen.de
                Article
                dxx026
                10.1093/intimm/dxx026
                5890895
                28498981
                f8bdf7c4-a2f8-478b-842f-9df35082a212
                © The Author 2017. Published by Oxford University Press on behalf of The Japanese Society for Immunology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 18 March 2017
                : 27 April 2017
                Page count
                Pages: 9
                Categories
                Invited Reviews

                Immunology
                alternative splicing,b cells,nuclear bodies,sequencing,t cells
                Immunology
                alternative splicing, b cells, nuclear bodies, sequencing, t cells

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