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Yi Xing - One of the best experts on this subject based on the ideXlab platform.
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identifying differential Alternative Splicing events from rna sequencing data using rnaseq mats
Methods of Molecular Biology, 2013Co-Authors: Juw Won Park, Collin Tokheim, Shihao Shen, Yi XingAbstract:: RNA sequencing (RNA-Seq) has emerged as a powerful and increasingly cost-effective technology for analysis of transcriptomes. RNA-Seq has several significant advantages over gene expression microarrays, including its high sensitivity and accuracy, broad dynamic range, nucleotide-level resolution, ability to detect novel mRNA transcripts, and ability to analyze pre-mRNA Alternative Splicing. A major application of RNA-Seq is to detect differential Alternative Splicing, i.e., differences in exon Splicing patterns among different biological conditions. We recently developed a statistical method multivariate analysis of transcript Splicing (MATS) for detecting differential Alternative Splicing events from RNA-Seq data. Here, we describe a computational pipeline RNASeq-MATS based on the MATS algorithm. This pipeline automatically detects and analyzes differential Alternative Splicing events corresponding to all major types of Alternative Splicing patterns from RNA-Seq data.
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mats a bayesian framework for flexible detection of differential Alternative Splicing from rna seq data
Nucleic Acids Research, 2012Co-Authors: Shihao Shen, Juw Won Park, Jian Huang, Kimberly Dittmar, Zhixiang Lu, Qing Zhou, Russ P Carstens, Yi XingAbstract:: Ultra-deep RNA sequencing has become a powerful approach for genome-wide analysis of pre-mRNA Alternative Splicing. We develop MATS (multivariate analysis of transcript Splicing), a bayesian statistical framework for flexible hypothesis testing of differential Alternative Splicing patterns on RNA-Seq data. MATS uses a multivariate uniform prior to model the between-sample correlation in exon Splicing patterns, and a Markov chain Monte Carlo (MCMC) method coupled with a simulation-based adaptive sampling procedure to calculate the P-value and false discovery rate (FDR) of differential Alternative Splicing. Importantly, the MATS approach is applicable to almost any type of null hypotheses of interest, providing the flexibility to identify differential Alternative Splicing events that match a given user-defined pattern. We evaluated the performance of MATS using simulated and real RNA-Seq data sets. In the RNA-Seq analysis of Alternative Splicing events regulated by the epithelial-specific Splicing factor ESRP1, we obtained a high RT-PCR validation rate of 86% for differential exon skipping events with a MATS FDR of <10%. Additionally, over the full list of RT-PCR tested exons, the MATS FDR estimates matched well with the experimental validation rate. Our results demonstrate that MATS is an effective and flexible approach for detecting differential Alternative Splicing from RNA-Seq data.
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Alternative Splicing and rna selection pressure evolutionary consequences for eukaryotic genomes
Nature Reviews Genetics, 2006Co-Authors: Yi XingAbstract:Genome-wide analyses of Alternative Splicing have established its nearly ubiquitous role in gene regulation in many organisms. Genome sequencing and comparative genomics have made it possible to look in detail at the evolutionary history of specific Alternative exons or splice sites, resulting in a flurry of publications in recent years. Here, we consider how Alternative Splicing has contributed to the evolution of modern genomes, and discuss constraints on evolution associated with Alternative Splicing that might have important medical implications.
Alberto R. Kornblihtt - One of the best experts on this subject based on the ideXlab platform.
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Alternative Splicing and Transcription Elongation in Plants
Frontiers Media S.A., 2019Co-Authors: Alberto R. Kornblihtt, Micaela Godoy A. HerzAbstract:Alternative Splicing and transcription elongation by RNA polymerase II (RNAPII) are two processes which are tightly connected. Splicing is a co-transcriptional process, and different experimental approaches show that Splicing is coupled to transcription in Drosophila, yeast and mammals. However, little is known about coupling of transcription and Alternative Splicing in plants. The kinetic coupling explains how changes in RNAPII elongation rate influence Alternative Splicing choices. Recent work in Arabidopsis shows that expression of a dominant negative transcription elongation factor, TFIIS, enhances exon inclusion. Furthermore, the Arabidopsis transcription elongation complex has been recently described, providing new information about elongation factors that interact with elongating RNAPII. Light regulates Alternative Splicing in plants through a chloroplast retrograde signaling. We have recently shown that light promotes RNAPII elongation in the affected genes, while in darkness elongation is lower. These changes in transcription are consistent with elongation causing the observed changes in Alternative Splicing. Altogether, these findings provide evidence that coupling between transcription and Alternative Splicing is an important layer of gene expression regulation in plants
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chromatin dna structure and Alternative Splicing
FEBS Letters, 2015Co-Authors: Nicolas Nieto Moreno, Manuel J. Muñoz, Luciana E Giono, Adrian Cambindo E Botto, Alberto R. KornblihttAbstract:Coupling of transcription and Alternative Splicing via regulation of the transcriptional elongation rate is a well-studied phenomenon. Template features that act as roadblocks for the progression of RNA polymerase II comprise histone modifications and variants, DNA-interacting proteins and chromatin compaction. These may affect Alternative Splicing decisions by inducing pauses or decreasing elongation rate that change the time-window for Splicing regulatory sequences to be recognized. Herein we discuss the evidence supporting the influence of template structural modifications on transcription and Splicing, and provide insights about possible roles of non-B DNA conformations on the regulation of Alternative Splicing.
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Alternative Splicing a pivotal step between eukaryotic transcription and translation
Nature Reviews Molecular Cell Biology, 2013Co-Authors: Alberto R. Kornblihtt, Ignacio E. Schor, Mariano Alló, Gwendal Dujardin, Ezequiel Petrillo, Manuel J. MuñozAbstract:Alternative Splicing was discovered simultaneously with Splicing over three decades ago. Since then, an enormous body of evidence has demonstrated the prevalence of Alternative Splicing in multicellular eukaryotes, its key roles in determining tissue- and species-specific differentiation patterns, the multiple post- and co-transcriptional regulatory mechanisms that control it, and its causal role in hereditary disease and cancer. The emerging evidence places Alternative Splicing in a central position in the flow of eukaryotic genetic information, between transcription and translation, in that it can respond not only to various signalling pathways that target the Splicing machinery but also to transcription factors and chromatin structure.
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the carboxy terminal domain of rna polymerase ii and Alternative Splicing
Trends in Biochemical Sciences, 2010Co-Authors: Manuel Munoz, Manuel De La Mata, Alberto R. KornblihttAbstract:Alternative Splicing is controlled by cis -regulatory sequences present in the pre-mRNA and their cognate trans -acting factors, as well as by its coupling to RNA polymerase II (pol II) transcription. A unique feature of this polymerase is the presence of a highly repetitive carboxy terminal domain (CTD), which is subject to multiple regulatory post-translational modifications. CTD phosphorylation events affect the transcriptional properties of pol II and the outcome of co-transcriptional Alternative Splicing by mediating the effects of Splicing factors and by modulating transcription elongation rates. Here, we discuss various examples of involvement of the CTD in Alternative Splicing regulation as well as the current methodological limitations in deciphering the detailed mechanisms of this process.
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a slow rna polymerase ii affects Alternative Splicing in vivo
Molecular Cell, 2003Co-Authors: Manuel De La Mata, Paula Cramer, Sebastian Kadener, Claudio R Alonso, Juan Pablo Fededa, Matias Blaustein, Federico Pelisch, David Bentley, Alberto R. KornblihttAbstract:Changes in promoter structure and occupation have been shown to modify the Splicing pattern of several genes, evidencing a coupling between transcription and Alternative Splicing. It has been proposed that the promoter effect involves modulation of RNA pol II elongation rates. The C4 point mutation of the Drosophila pol II largest subunit confers on the enzyme a lower elongation rate. Here we show that expression of a human equivalent to Drosophila's C4 pol II in human cultured cells affects Alternative Splicing of the fibronectin EDI exon and adenovirus E1a pre-mRNA. Most importantly, reSplicing of the Hox gene Ultrabithorax is stimulated in Drosophila embryos mutant for C4, which demonstrates the transcriptional control of Alternative Splicing on an endogenous gene. These results provide a direct proof for the elongation control of Alternative Splicing in vivo.
Peter Scheiffele - One of the best experts on this subject based on the ideXlab platform.
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A Sam68-dependent Alternative Splicing program shapes postsynaptic protein complexes.
The European journal of neuroscience, 2019Co-Authors: Harald Witte, Dietmar Schreiner, Peter ScheiffeleAbstract:Alternative Splicing is one of the key mechanisms to increase the diversity of cellular transcriptomes, thereby expanding the coding capacity of the genome. This diversity is of particular importance in the nervous system with its elaborated cellular networks. Sam68, a member of the Signal Transduction Associated RNA-binding (STAR) family of RNA-binding proteins, is expressed in the developing and mature nervous system but its neuronal functions are poorly understood. Here, we perform genome-wide mapping of the Sam68-dependent Alternative Splicing program in mice. We find that Sam68 is required for the regulation of a set of Alternative Splicing events in pre-mRNAs encoding several postsynaptic scaffolding molecules that are central to the function of GABAergic and glutamatergic synapses. These components include Collybistin (Arhgef9), Gephyrin (Gphn), and Densin-180 (Lrrc7). Sam68-regulated Lrrc7 variants engage in differential protein interactions with signalling proteins, thus, highlighting a contribution of the Sam68 Splicing program to shaping synaptic complexes. These findings suggest an important role for Sam68-dependent Alternative Splicing in the regulation of synapses in the central nervous system.
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sam68 regulates neuronal activity dependent Alternative Splicing of neurexin 1
Cell, 2011Co-Authors: Takatoshi Iijima, Harald Witte, Yoko Hannoiijima, Timo Glatter, Stephane Richard, Peter ScheiffeleAbstract:The assembly of synapses and neuronal circuits relies on an array of molecular recognition events and their modification by neuronal activity. Neurexins are a highly polymorphic family of synaptic receptors diversified by extensive Alternative Splicing. Neurexin variants exhibit distinct isoform-specific biochemical interactions and synapse assembly functions, but the mechanisms governing splice isoform choice are not understood. We demonstrate that Nrxn1 Alternative Splicing is temporally and spatially controlled in the mouse brain. Neuronal activity triggers a shift in Nrxn1 splice isoform choice via calcium/calmodulin-dependent kinase IV signaling. Activity-dependent Alternative Splicing of Nrxn1 requires the KH-domain RNA-binding protein SAM68 that associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent Alternative Splicing in the central nervous system.
Manuel Ares - One of the best experts on this subject based on the ideXlab platform.
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context dependent control of Alternative Splicing by rna binding proteins
Nature Reviews Genetics, 2014Co-Authors: Xiangdong Fu, Manuel AresAbstract:RNA-binding proteins (RBPs) influence Alternative Splicing in a highly context-sensitive and combinatorial manner, and it is therefore difficult to predict their actions on the basis of genomic sequence. However, recent progress in understanding Alternative Splicing, particularly using global approaches, has revealed new sets of rules for deciphering these patterns. This Review outlines the function of RBPs at different levels and describes the emerging rules of Alternative Splicing.
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context dependent control of Alternative Splicing by rna binding proteins
Nature Reviews Genetics, 2014Co-Authors: Manuel AresAbstract:Sequence-specific RNA-binding proteins (RBPs) bind to pre-mRNA to control Alternative Splicing, but it is not yet possible to read the 'Splicing code' that dictates Splicing regulation on the basis of genome sequence. Each Alternative Splicing event is controlled by multiple RBPs, the combined action of which creates a distribution of Alternatively spliced products in a given cell type. As each cell type expresses a distinct array of RBPs, the interpretation of regulatory information on a given RNA target is exceedingly dependent on the cell type. RBPs also control each other's functions at many levels, including by mutual modulation of their binding activities on specific regulatory RNA elements. In this Review, we describe some of the emerging rules that govern the highly context-dependent and combinatorial nature of Alternative Splicing regulation.
Thomas C Sudhof - One of the best experts on this subject based on the ideXlab platform.
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Alternative Splicing of presynaptic neurexins differentially controls postsynaptic nmda and ampa receptor responses
Neuron, 2019Co-Authors: Jason Aoto, Thomas C Sudhof, Jinye DaiAbstract:Summary AMPA- and NMDA-type glutamate receptors mediate distinct postsynaptic signals that differ characteristically among synapses. How postsynaptic AMPA- and NMDA-receptor levels are regulated, however, remains unclear. Using newly generated conditional knockin mice that enable genetic control of neurexin Alternative Splicing, we show that in hippocampal synapses, Alternative Splicing of presynaptic neurexin-1 at splice site 4 (SS4) dramatically enhanced postsynaptic NMDA-receptor-mediated, but not AMPA-receptor-mediated, synaptic responses without altering synapse density. In contrast, Alternative Splicing of neurexin-3 at SS4 suppressed AMPA-receptor-mediated, but not NMDA-receptor-mediated, synaptic responses, while Alternative Splicing of neurexin-2 at SS4 had no effect on NMDA- or AMPA-receptor-mediated responses. Presynaptic overexpression of the neurexin-1β and neurexin-3β SS4+ splice variants, but not of their SS4− splice variants, replicated the respective SS4+ knockin phenotypes. Thus, different neurexins perform distinct nonoverlapping functions at hippocampal synapses that are independently regulated by Alternative Splicing. These functions transsynaptically control NMDA and AMPA receptors, thereby mediating presynaptic control of postsynaptic responses.
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developmentally regulated Alternative Splicing in a novel synaptojanin
Journal of Biological Chemistry, 1998Co-Authors: Mikhail Khvotchev, Thomas C SudhofAbstract:Phosphatidylinositol phosphates (PIPs) perform central functions in signal transduction and membrane traffic. Synaptojanin is a PIP 5-phosphatase that is expressed in a brain-specific and a ubiquitous splice variants and is thought to constitute the major PIP 5-phosphatase in mammalian brain (Woscholski, R., Finan, P.M., Radley, E., Totty, N.F., Sterling, A.E., Hsuan, J.J., Waterfield, M. D., and Parker, P. J. (1997) J. Biol. Chem. 272, 9625-9628). We now describe synaptojanin 2, a novel isoform of synaptojanin that, similar to synaptojanin 1, contains an N-terminal SAC1-like sequence and a central 5-phosphatase domain but a distinct, unique C-terminal sequence. Transfection studies demonstrated that synaptojanin 2, like synaptojanin 1, is an active PIP phosphatase. An interesting feature of synaptojanin 1 is the presence of a long open reading frame in the 3' region of the brain mRNA that in non-brain tissues is joined to the coding region by Alternative Splicing, resulting in a shorter synaptojanin 1 form in brain and a longer form in peripheral tissues (Ramjaun, A. R., and McPherson, P. S. (1996) J. Biol. Chem. 271, 24856-24861). Although it exhibits no homology to synaptojanin 1 in this region, synaptojanin 2 also contains an open reading frame in the 3' region that is subject to Alternative Splicing. Similar to synaptojanin 1, Alternative Splicing of synaptojanin 2 is tissue-specific and creates a shorter isoform expressed in brain and a longer form in peripheral tissues. The similar Alternative Splicing of two homologous proteins in a region of non-homology raises the possibility of evolutionary convergence and supports the significance of the variants. Analysis of mRNAs from three brain regions at different developmental stages revealed that Alternative Splicing of synaptojanin 2 is a developmentally late event, occurring only after the first postnatal week after the generation of neurons and initial synaptogenesis.