Splicing Factor SRp30c Interaction with Y-box Protein-1 Confers Nuclear YB-1 Shuttling and Alternative Splice Site Selection

AbstractMotivationAlternative splice site selection is inherently competitive and the probability of a given splice site to be used also depends strongly on the strength of neighboring sites. Here we present a new model named Competitive Splice Site Model (COSSMO), which explicitly models these competitive effects and predict the PSI distribution over any number of putative splice sites. We model an alternative splicing event as the choice of a 3’ acceptor site conditional on a fixed upstream 5’ donor site, or the choice of a 5’ donor site conditional on a fixed 3’ acceptor site. We build four different architectures that use convolutional layers, communication layers, LSTMS, and residual networks, respectively, to learn relevant motifs from sequence alone. We also construct a new dataset from genome annotations and RNA-Seq read data that we use to train our model.ResultsCOSSMO is able to predict the most frequently used splice site with an accuracy of 70% on unseen test data, and achieve an R2 of 60% in modeling the PSI distribution. We visualize the motifs that COSSMO learns from sequence and show that COSSMO recognizes the consensus splice site sequences as well as many known splicing factors with high specificity.AvailabilityOur dataset is available from http://cossmo.deepgenomics.com.Contactfrey@deepgenomics.comSupplementary informationSupplementary data are available at Bioinformatics online.

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COSSMO: predicting competitive alternative splice site selection using deep learning

Bioinformatics ◽

10.1093/bioinformatics/bty244 ◽

2018 ◽

Vol 34 (13) ◽

pp. i429-i437 ◽

Cited By ~ 18

Author(s):

Hannes Bretschneider ◽

Shreshth Gandhi ◽

Amit G Deshwar ◽

Khalid Zuberi ◽

Brendan J Frey

Keyword(s):

Deep Learning ◽

Alternative Splice ◽

Splice Site ◽

Site Selection ◽

Splice Site Selection ◽

Alternative Splice Site

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A native RNA secondary structure controls alternative splice-site selection and generates two human growth hormone isoforms.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)42125-4 ◽

1992 ◽

Vol 267 (21) ◽

pp. 14902-14908 ◽

Cited By ~ 1

Author(s):

P.A. Estes ◽

N.E. Cooke ◽

S.A. Liebhaber

Keyword(s):

Growth Hormone ◽

Secondary Structure ◽

Alternative Splice ◽

Human Growth Hormone ◽

Splice Site ◽

Site Selection ◽

Rna Secondary Structure ◽

Human Growth ◽

Splice Site Selection ◽

Alternative Splice Site

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Co-transcriptional commitment to alternative splice site selection

Nucleic Acids Research ◽

10.1093/nar/26.24.5568 ◽

1998 ◽

Vol 26 (24) ◽

pp. 5568-5572 ◽

Cited By ~ 119

Author(s):

G. Roberts

Keyword(s):

Alternative Splice ◽

Splice Site ◽

Site Selection ◽

Splice Site Selection ◽

Alternative Splice Site

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Alternative Splice Site Selection

Alternative pre-mRNA Splicing ◽

10.1002/9783527636778.ch8 ◽

2012 ◽

pp. 93-107

Author(s):

Miguel B. Coelho ◽

Christopher W. J. Smith

Keyword(s):

Alternative Splice ◽

Splice Site ◽

Site Selection ◽

Splice Site Selection ◽

Alternative Splice Site

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The anti-angiogenic isoforms of VEGF in health and disease

Biochemical Society Transactions ◽

10.1042/bst0371207 ◽

2009 ◽

Vol 37 (6) ◽

pp. 1207-1213 ◽

Cited By ~ 76

Author(s):

Yan Qiu ◽

Coralie Hoareau-Aveilla ◽

Sebastian Oltean ◽

Steven J. Harper ◽

David O. Bates

Keyword(s):

Splice Site ◽

Site Selection ◽

Age Related Macular Degeneration ◽

Splicing Factor ◽

Splice Site Selection ◽

Age Related ◽

Normal Human ◽

Radical Revision

Anti-angiogenic VEGF (vascular endothelial growth factor) isoforms, generated from differential splicing of exon 8, are widely expressed in normal human tissues but down-regulated in cancers and other pathologies associated with abnormal angiogenesis (cancer, diabetic retinopathy, retinal vein occlusion, the Denys–Drash syndrome and pre-eclampsia). Administration of recombinant VEGF165b inhibits ocular angiogenesis in mouse models of retinopathy and age-related macular degeneration, and colorectal carcinoma and metastatic melanoma. Splicing factors and their regulatory molecules alter splice site selection, such that cells can switch from the anti-angiogenic VEGFxxxb isoforms to the pro-angiogenic VEGFxxx isoforms, including SRp55 (serine/arginine protein 55), ASF/SF2 (alternative splicing factor/splicing factor 2) and SRPK (serine arginine domain protein kinase), and inhibitors of these molecules can inhibit angiogenesis in the eye, and splice site selection in cancer cells, opening up the possibility of using splicing factor inhibitors as novel anti-angiogenic therapeutics. Endogenous anti-angiogenic VEGFxxxb isoforms are cytoprotective for endothelial, epithelial and neuronal cells in vitro and in vivo, suggesting both an improved safety profile and an explanation for unpredicted anti-VEGF side effects. In summary, C-terminal distal splicing is a key component of VEGF biology, overlooked by the vast majority of publications in the field, and these findings require a radical revision of our understanding of VEGF biology in normal human physiology.

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The concentration of B52, an essential splicing factor and regulator of splice site choice in vitro, is critical for Drosophila development.

Molecular and Cellular Biology ◽

10.1128/mcb.14.8.5360 ◽

1994 ◽

Vol 14 (8) ◽

pp. 5360-5370 ◽

Cited By ~ 25

Author(s):

M E Kraus ◽

J T Lis

Keyword(s):

Alternative Splice ◽

Splice Site ◽

Developmental Stages ◽

Immunoblot Analysis ◽

Splicing Factor ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Alternative Splice Site

B52 is a Drosophila melanogaster protein that plays a role in general and alternative splicing in vitro. It is homologous to the human splicing factor ASF/SF2 which is essential for an early step(s) in spliceosome assembly in vitro and also regulates 5' and 3' alternative splice site choice in a concentration-dependent manner. In vitro, B52 can function as both a general splicing factor and a regulator of 5' alternative splice site choice. Its activity in vivo, however, is largely uncharacterized. In this study, we have further characterized B52 in vivo. Using Western blot (immunoblot) analysis and whole-mount immunofluorescence, we demonstrate that B52 is widely expressed throughout development, although some developmental stages and tissues appear to have higher B52 levels than others do. In particular, B52 accumulates in ovaries, where it is packaged into the developing egg and is localized to nuclei by the late blastoderm stage of embryonic development. We also overexpressed this protein in transgenic flies in a variety of developmental and tissue-specific patterns to examine the effects of altering the concentration of this splicing factor in vivo. We show that, in many cell types, changing the concentration of B52 adversely affects the development of the organism. We discuss the significance of these observations with regard to previous in vitro results.

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