An analysis of tissue-specific alternative splicing at the protein level.
An analysis of tissue-specific alternative splicing at the protein level.
复制标题
在蛋白质水平上对组织特异性替代剪接的分析。
DOI：
10.1371/journal.pcbi.1008287
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发表时间：
2020-10
影响因子：
4.3
通讯作者：
Tress ML
中科院分区：
文献类型：
--
作者：
Rodriguez JM;Pozo F;di Domenico T;Vazquez J;Tress ML
选择性剪接的作用是细胞生物学中尚未回答的重大问题之一。有强有力的证据表明，在转录水平的选择性剪接，和转录组学实验表明，许多剪接事件是组织特异性的。有人认为，选择性剪接的进化是为了重塑组织特异性蛋白质-蛋白质网络。在这里，我们调查了大规模蛋白质组学分析中检测到的剪接异构体之间的组织特异性剪接的证据。虽然支持选择性剪接的数据在蛋白质水平上是有限的，但我们可以在蛋白质组学数据中检测到的少量选择性剪接事件中出现了清晰的模式。超过三分之一的这些剪接事件是组织特异性的，大多数是古老的：在蛋白质组学和RNAseq分析中，超过95%的组织特异性剪接事件在至少4亿年前的叶鳍鱼祖先之前进化。相比之下，人类基因组中四分之三的替代外显子出现在灵长类谱系中，因此我们的结果不能外推到整个基因组。蛋白质组学分析中的组织特异性替代蛋白质形式在神经和肌肉组织中特别丰富，它们的基因具有与细胞骨架以及肌肉纤维结构或细胞-细胞连接相关的作用。我们的研究结果表明，这种保守的组织特异性选择性剪接可能在脊椎动物大脑和心脏的发育中发挥了作用。我们手动策划了一组在大规模基于组织的蛋白质组学实验中检测到的255个剪接事件，发现超过三分之一的剪接事件具有显著的组织特异性差异。在蛋白质水平上具有显著组织特异性的事件是高度保守的;近75%的事件是在4亿多年前进化的。我们发现组织特异性剪接证据最多的组织是神经组织和心脏组织。在这两种组织中具有组织特异性事件的基因具有与脑和心脏组织中的重要细胞结构相关的功能。这些剪接事件可能对脊椎动物心脏和肌肉的发育至关重要。然而，我们的数据集可能不能代表替代外显子作为一个整体。我们发现，大多数组织特异性剪接是高度保守的，但在人类基因组中只有5%的注释的替代外显子是古老的。超过四分之三的替代外显子是灵长类衍生的。虽然分析没有提供一个明确的答案选择性剪接的功能作用的问题，我们的研究结果表明，选择性剪接变异体可能发挥了重要作用，在脊椎动物的大脑和心脏组织的进化。
The role of alternative splicing is one of the great unanswered questions in cellular biology. There is strong evidence for alternative splicing at the transcript level, and transcriptomics experiments show that many splice events are tissue specific. It has been suggested that alternative splicing evolved in order to remodel tissue-specific protein-protein networks. Here we investigated the evidence for tissue-specific splicing among splice isoforms detected in a large-scale proteomics analysis. Although the data supporting alternative splicing is limited at the protein level, clear patterns emerged among the small numbers of alternative splice events that we could detect in the proteomics data. More than a third of these splice events were tissue-specific and most were ancient: over 95% of splice events that were tissue-specific in both proteomics and RNAseq analyses evolved prior to the ancestors of lobe-finned fish, at least 400 million years ago. By way of contrast, three in four alternative exons in the human gene set arose in the primate lineage, so our results cannot be extrapolated to the whole genome. Tissue-specific alternative protein forms in the proteomics analysis were particularly abundant in nervous and muscle tissues and their genes had roles related to the cytoskeleton and either the structure of muscle fibres or cell-cell connections. Our results suggest that this conserved tissue-specific alternative splicing may have played a role in the development of the vertebrate brain and heart. We manually curated a set of 255 splice events detected in a large-scale tissue-based proteomics experiment and found that more than a third had evidence of significant tissue-specific differences. Events that were significantly tissue-specific at the protein level were highly conserved; almost 75% evolved over 400 million years ago. The tissues in which we found most evidence for tissue-specific splicing were nervous tissues and cardiac tissues. Genes with tissue-specific events in these two tissues had functions related to important cellular structures in brain and heart tissues. These splice events may have been essential for the development of vertebrate heart and muscle. However, our data set may not be representative of alternative exons as a whole. We found that most tissue specific splicing was strongly conserved, but just 5% of annotated alternative exons in the human gene set are ancient. More than three quarters of alternative exons are primate-derived. Although the analysis does not provide a definitive answer to the question of the functional role of alternative splicing, our results do indicate that alternative splice variants may have played a significant part in the evolution of brain and heart tissues in vertebrates.
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影响因子：
64.8
作者：
Kim, Min-Sik;Pinto, Sneha M.;Getnet, Derese;Nirujogi, Raja Sekhar;Manda, Srikanth S.;Chaerkady, Raghothama;Madugundu, Anil K.;Kelkar, Dhanashree S.;Isserlin, Ruth;Jain, Shobhit;Thomas, Joji K.;Muthusamy, Babylakshmi;Leal-Rojas, Pamela;Kumar, Praveen;Sahasrabuddhe, Nandini A.;Balakrishnan, Lavanya;Advani, Jayshree;George, Bijesh;Renuse, Santosh;Selvan, Lakshmi Dhevi N.;Patil, Arun H.;Nanjappa, Vishalakshi;Radhakrishnan, Aneesha;Prasad, Samarjeet;Subbannayya, Tejaswini;Raju, Rajesh;Kumar, Manish;Sreenivasamurthy, Sreelakshmi K.;Marimuthu, Arivusudar;Sathe, Gajanan J.;Chavan, Sandip;Datta, Keshava K.;Subbannayya, Yashwanth;Sahu, Apeksha;Yelamanchi, Soujanya D.;Jayaram, Savita;Rajagopalan, Pavithra;Sharma, Jyoti;Murthy, Krishna R.;Syed, Nazia;Goel, Renu;Khan, Aafaque A.;Ahmad, Sartaj;Dey, Gourav;Mudgal, Keshav;Chatterjee, Aditi;Huang, Tai-Chung;Zhong, Jun;Wu, Xinyan;Shaw, Patrick G.;Freed, Donald;Zahari, Muhammad S.;Mukherjee, Kanchan K.;Shankar, Subramanian;Mahadevan, Anita;Lam, Henry;Mitchell, Christopher J.;Shankar, Susarla Krishna;Satishchandra, Parthasarathy;Schroeder, John T.;Sirdeshmukh, Ravi;Maitra, Anirban;Leach, Steven D.;Drake, Charles G.;Halushka, Marc K.;Prasad, T. S. Keshava;Hruban, Ralph H.;Kerr, Candace L.;Bader, Gary D.;Iacobuzio-Donahue, Christine A.;Gowda, Harsha;Pandey, Akhilesh
通讯作者：
Pandey, Akhilesh
影响因子：
12.3
作者：
Gonzàlez-Porta M;Frankish A;Rung J;Harrow J;Brazma A
通讯作者：
Brazma A
影响因子：
3.5
作者：
Kelemen O;Convertini P;Zhang Z;Wen Y;Shen M;Falaleeva M;Stamm S
通讯作者：
Stamm S
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
14.9
作者：
Deutsch EW;Csordas A;Sun Z;Jarnuczak A;Perez-Riverol Y;Ternent T;Campbell DS;Bernal-Llinares M;Okuda S;Kawano S;Moritz RL;Carver JJ;Wang M;Ishihama Y;Bandeira N;Hermjakob H;Vizcaíno JA
通讯作者：
Vizcaíno JA