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BIOSYSTEMS 2018年 164卷 39-48页

作者： Baralle, Marco Baralle, Francisco Ernesto Int Ctr Genet Engn & Biotechnol Padriciano 99 Trieste Italy

This issue dedicated to the code of life tackles very challenging and open questions in Biology. The genetic code, brilliantly uncovered over 50 years ago is an example of a univocal biological code. In fact, except for very few and marginal variations, it is the same from bacteria to man, the RNA stretch: 5' GUGUUC 3' reads as the dipeptide: Val-Phe in bacteria, in yeast, in Arabidopsis, in zebra fish, in mouse and in human. A degree of ambiguity is possible if mutations are introduced in the tRNAs in a way that the anticodon reads one amino acid but the aminoacyl-transferase attaches a different one onto the tRNA. These were the very useful suppressor genes that aided greatly the study of bacterial genetics. Other biological codes however, are more akin to social codes and are less amenable to an unambiguous deciphering. Legal and ethical codes, weather we like it or not, are flexible and depend on the structure and history of the society that has produced them, as well as a specific point in time. The codes that govern RNA splicing have similar characteristics. In fact, the splicing code depends on a myriad of different factors that in part are influenced by the background in which they are read such as different cells, tissues or developmental stages. Given the complexity of the splicing process, the construction of an algorithm that can define exons or their fate with certainty has not yet been achieved. However a substantial amount of information towards the deciphering of the splicing code has been gathered and in this manuscript we summarize the point reached. (C) 2017 Elsevier B.V. All rights reserved.

关键词： splicing code Alternative splicing Aplicing regulators RNA binding proteins splicing regulatory elements

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In silico to in vivo splicing analysis using splicing code models

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METHODS 2014年第1期67卷 3-12页

作者： Gazzara, Matthew R. Vaquero-Garcia, Jorge Lynch, Kristen W. Barash, Yoseph Univ Penn Dept Genet Perelman Sch Med Philadelphia PA 19104 USA Univ Penn Dept Biochem & Biophys Perelman Sch Med Philadelphia PA 19104 USA Univ Penn Dept Comp & Informat Sci Philadelphia PA 19104 USA

With the growing appreciation of RNA splicing's role in gene regulation, development, and disease, researchers from diverse fields find themselves investigating exons of interest. Commonly, researchers are interested in knowing if an exon is alternatively spliced, if it is differentially included in specific tissues or in developmental stages, and what regulatory elements control its inclusion. An important step towards the ability to perform such analysis in silico was made with the development of computational splicing code models. Aimed as a practical how-to guide, we demonstrate how researchers can now use these code models to analyze a gene of interest, focusing on Bin1 as a case study. Bridging integrator 1 (BIN1) is a nucleocytoplasmic adaptor protein known to be functionally regulated through alternative splicing in a tissue-specific manner. Specific Bin1 isoforms have been associated with muscular diseases and cancers, making the study of its splicing regulation of wide interest. Using AVISPA, a recently released web tool based on splicing code models, we show that many Bin1 tissue-dependent isoforms are correctly predicted, along with many of its known regulators. We review the best practices and constraints of using the tool, demonstrate how AVISPA is used to generate high confidence novel regulatory hypotheses, and experimentally validate predicted regulators of Bin1 alternative splicing. (C) 2013 Elsevier Inc. All rights reserved.

关键词： Alternative splicing splicing code BIN1 AVISPA Centronuclear myopathy (CNM) Myotonic dystrophy (DM)

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Enhanced Integrated Gradients: improving interpretability of deep learning models using splicing codes as a case study

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GENOME BIOLOGY 2020年第1期21卷 1页

作者： Jha, Anupama Aicher, Joseph K. Gazzara, Matthew R. Singh, Deependra Barash, Yoseph Univ Penn Sch Engn & Appl Sci Dept Comp & Informat Sci Philadelphia PA 19104 USA Univ Penn Perelman Sch Med Dept Genet Philadelphia PA 19104 USA

Despite the success and fast adaptation of deep learning models in biomedical domains, their lack of interpretability remains an issue. Here, we introduce Enhanced Integrated Gradients (EIG), a method to identify significant features associated with a specific prediction task. Using RNA splicing prediction as well as digit classification as case studies, we demonstrate that EIG improves upon the original Integrated Gradients method and produces sets of informative features. We then apply EIG to identify A1CF as a key regulator of liver-specific alternative splicing, supporting this finding with subsequent analysis of relevant A1CF functional (RNA-seq) and binding data (PAR-CLIP).

关键词： Deep learning splicing code Interpretation Liver-specific splicing A1CF

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Removing quote marks from the RNA polymerase II CTD 'code'

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BIOSYSTEMS 2021年 207卷 104468-104468页

作者： Dieci, Giorgio Univ Parma Dept Chem Life Sci & Environm Sustainabil Parco Area Sci 23-A I-43124 Parma Italy

In eukaryotes, RNA polymerase II (Pol II) is responsible for the synthesis of all mRNAs and myriads of short and long untranslated RNAs, whose fabrication involves close spatiotemporal coordination between transcription, RNA processing and chromatin modification. Crucial for such a coordination is an unusual C-terminal domain (CTD) of the Pol II largest subunit, made of tandem repetitions (26 in yeast, 52 in chordates) of the heptapeptide with the consensus sequence YSPTSPS. Although largely unstructured and with poor sequence content, the Pol II CTD derives its extraordinary functional versatility from the fact that each amino acid in the heptapeptide can be posttranslationally modified, and that different combinations of CTD covalent marks are specifically recognized by different protein binding partners. These features have led to propose the existence of a Pol II CTD code, but this expression is generally used by authors with some caution, revealed by the frequent use of quote marks for the word 'code'. Based on the theoretical framework of code biology, it is argued here that the Pol II CTD modification system meets the requirements of a true organic code, where different CTD modification states represent organic signs whose organic meanings are biological reactions contributing to the many facets of RNA biogenesis in coordination with RNA synthesis by Pol II. Importantly, the Pol II CTD code is instantiated by adaptor proteins possessing at least two distinct domains, one of which devoted to specific recognition of CTD modification profiles. Furthermore, code rules can be altered by experimental interchange of CTD recognition domains of different adaptor proteins, a fact arguing in favor of the arbitrariness, and thus bona fide character, of the Pol II CTD code. Since the growing family of CTD adaptors includes RNA binding proteins and histone modification complexes, the Pol II CTD code is by its nature integrated with other organic codes, in particular the sp

关键词： RNA polymerase II Transcription Chromatin CTD code Histone code splicing code Liquid-liquid phase separation Intrinsically disordered regions Protein tandem repeats

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Myocardin regulates exon usage in smooth muscle cells through induction of splicing regulatory factors

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CELLULAR AND MOLECULAR LIFE SCIENCES 2022年第8期79卷 459-459页

作者： Liu, Li Kryvokhyzha, Dmytro Rippe, Catarina Jacob, Aishwarya Borreguero-Munoz, Andrea Stenkula, Karin G. Hansson, Ola Smith, Christopher W. J. Fisher, Steven A. Sward, Karl Dept Expt Med Sci BMC D12 SE-22184 Lund Sweden Guangzhou Med Univ Qingyuan Peoples Hosp Affiliated Hosp 6 Dept Urol Qingyuan Peoples R China Lund Univ Diabet Ctr CRC Dept Clin Sci S-21428 Malmo Sweden Univ Cambridge Dept Biochem Cambridge England Univ Helsinki Inst Mol Med Finland FIMM Helsinki Finland Univ Maryland Dept Med Cardiol & Physiol & Biophys Baltimore MD 21201 USA

Differentiation of smooth muscle cells (SMCs) depends on serum response factor (SRF) and its co-activator myocardin (MYOCD). The role of MYOCD for the SMC program of gene transcription is well established. In contrast, the role of MYOCD in control of SMC-specific alternative exon usage, including exon splicing, has not been explored. In the current work we identified four splicing factors (MBNL1, RBPMS, RBPMS2, and RBFOX2) that correlate with MYOCD across human SMC tissues. Forced expression of MYOCD family members in human coronary artery SMCs in vitro upregulated expression of these splicing factors. For global profiling of transcript diversity, we performed RNA-sequencing after MYOCD transduction. We analyzed alternative transcripts with three different methods. Exon-based analysis identified 1637 features with differential exon usage. For example, usage of 3 ' exons in MYLK that encode telokin increased relative to 5 ' exons, as did the 17 kDa telokin to 130 kDa MYLK protein ratio. Dedicated event-based analysis identified 239 MYOCD-driven splicing events. Events involving MBNL1, MCAM, and ACTN1 were among the most prominent, and this was confirmed using variant-specific PCR analyses. In support of a role for RBPMS and RBFOX2 in MYOCD-driven splicing we found enrichment of their binding motifs around differentially spliced exons. Moreover, knockdown of either RBPMS or RBFOX2 antagonized splicing events stimulated by MYOCD, including those involving ACTN1, VCL, and MBNL1. Supporting an in vivo role of MYOCD-SRF-driven splicing, we demonstrate altered Rbpms expression and splicing in inducible and SMC-specific Srf knockout mice. We conclude that MYOCD-SRF, in part via RBPMS and RBFOX2, induce a program of differential exon usage and alternative splicing as part of the broader program of SMC differentiation.

关键词： splicing code Actin-binding Focal adhesion Heart Differentiation

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A chromatin code for alternative splicing involving a putative association between CTCF and HP1α proteins

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BMC BIOLOGY 2015年第1期13卷 31-31页

作者： Agirre, Eneritz Bellora, Nicolas Allo, Mariano Pages, Amadis Bertucci, Paola Kornblihtt, Alberto R. Eyras, Eduardo Univ Pompeu Fabra E-08003 Barcelona Spain Univ Buenos Aires Fac Ciencias Exactas & Nat CONICET IFIBYNE Buenos Aires DF Argentina Ctr Genom Regulat E-08003 Barcelona Spain Catalan Inst Res & Adv Studies ICREA E-08010 Barcelona Spain

Background: Alternative splicing is primarily controlled by the activity of splicing factors and by the elongation of the RNA polymerase II (RNAPII). Recent experiments have suggested a new complex network of splicing regulation involving chromatin, transcription and multiple protein factors. In particular, the CCCTC-binding factor (CTCF), the Argonaute protein AGO1, and members of the heterochromatin protein 1 (HP1) family have been implicated in the regulation of splicing associated with chromatin and the elongation of RNAPII. These results raise the question of whether these proteins may associate at the chromatin level to modulate alternative splicing. Results: Using chromatin immunoprecipitation sequencing (ChIP-Seq) data for CTCF, AGO1, HP1 alpha, H3K27me3, H3K9me2, H3K36me3, RNAPII, total H3 and 5metC and alternative splicing arrays from two cell lines, we have analyzed the combinatorial code of their binding to chromatin in relation to the alternative splicing patterns between two cell lines, MCF7 and MCF10. Using Machine Learning techniques, we identified the changes in chromatin signals that are most significantly associated with splicing regulation between these two cell lines. Moreover, we have built a map of the chromatin signals on the pre-mRNA, that is, a chromatin-based RNA-map, which can explain 606 (68.55%) of the regulated events between MCF7 and MCF10. This chromatin code involves the presence of HP1 alpha, CTCF, AGO1, RNAPII and histone marks around regulated exons and can differentiate patterns of skipping and inclusion. Additionally, we found a significant association of HP1 alpha and CTCF activities around the regulated exons and a putative DNA binding site for HP1 alpha. Conclusions: Our results show that a considerable number of alternative splicing events could have a chromatin-dependent regulation involving the association of HP1 alpha and CTCF near regulated exons. Additionally, we find further evidence for the involvement of HP1 alpha a

关键词： Chromatin splicing Histones splicing code

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An exon-centric perspective

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BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE 2012年第5期90卷 603-612页

作者： Blencowe, Benjamin J. Univ Toronto Banting & Best Dept Med Res Donnelly Ctr Toronto ON M5S 3E1 Canada Univ Toronto Dept Mol Genet Donnelly Ctr Toronto ON M5S 3E1 Canada

During the past ten years, remarkable progress has been made in our understanding of the complexity and regulation of alternative splicing. The generation of large datasets of quantitative alternative splicing profiling information has revealed that transcripts from at least 95% of multi-exon human genes undergo alternative splicing, and that thousands of exons in mammalian transcriptomes are subject to striking regulatory patterns. Together with advanced computational methods, these datasets have enabled the inference of a predictive code for tissue-dependent alternative splicing. This code has further provided new insight into splicing regulatory mechanisms. Collectively, these approaches are revealing the existence of discrete networks of exons that are coordinately regulated in diverse biologically normal and disease contexts. A major challenge ahead is to systematically determine the functions of exons comprising these exon networks as well as the factors and mechanisms responsible for their regulation. This perspective provides an account of progress in these areas and also discusses future avenues of exon-centric exploration.

关键词： alternative splicing transcriptomics splicing code exon networks

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Alternative splicing and disease

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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 2009年第1期1792卷 14-26页

作者： Tazi, Jamal Bakkour, Nadia Stamm, Stefan Univ Kentucky Coll Med Dept Mol & Cellular Biochem Lexington KY 40536 USA Univ Montpellier 2 Inst Mol Genet CNRS F-34095 Montpellier 5 France

Almost all protein-coding genes are spliced and their majority is alternatively spliced. Alternative splicing is a key element in eukaryotic gene expression that increases the coding capacity of the human genome and an increasing number of examples illustrates that the selection of wrong splice sites causes human disease. A fine-tuned balance of factors regulates splice site selection. Here, we discuss well-studied examples that show how a disturbance of this balance can cause human disease. The rapidly emerging knowledge of splicing regulation now allows the development of treatment options. (C) 2008 Elsevier B.V. All rights reserved.

关键词： Alternative splicing Disease splicing code Mutation

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