Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches
Key Points Alternative splicing is a crucial mechanism for gene regulation and for generating proteomic diversity, which allows individual genes to generate multiple mature mRNA isoforms that can be translated into functionally different proteins. Alternative splicing can be regulated at different s...
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| Veröffentlicht in: | Nature reviews. Molecular cell biology 2009-11, Vol.10 (11), p.741-754 |
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| creator | Chen, Mo Manley, James L. |
| description | Key Points
Alternative splicing is a crucial mechanism for gene regulation and for generating proteomic diversity, which allows individual genes to generate multiple mature mRNA isoforms that can be translated into functionally different proteins. Alternative splicing can be regulated at different stages of spliceosome assembly and by different mechanisms.
Splice site recognition of alternative exons is frequently regulated by cooperative interactions between factors such as SR (Ser–Arg) proteins and heterogeneous nuclear ribonucleoprotein particles (hnRNPs), which have lower affinities and sequence specificities. Splice site selection is also influenced by the secondary structure of mRNAs.
Two models have been proposed to explain the role of RNA polymerase II in alternative splicing regulation: a recruitment model and a kinetic model, and the two models are not mutually exclusive.
Alternative splicing, including tissue-specific alternative splicing, is an extremely common regulatory mechanism. However, the number of known sequence-specific alternative splicing factors ( |
| doi_str_mv | 10.1038/nrm2777 |
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| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2958924</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A211175586</galeid><sourcerecordid>A211175586</sourcerecordid><originalsourceid>FETCH-LOGICAL-c594t-de35f89b173949d146a6e8ef5dbb51382eca70d812f71428eb8d0bf9fec0bee33</originalsourceid><addsrcrecordid>eNptkltrFTEUhQdRbK3iP5Cg4OXh1FxmJhkfhFK8FCqCl1dDJrMzJyWTnGbPFP33ppxD6ymSh4S9vr1CVnZVPWX0mFGh3sY8cSnlveqQ1ZKtKFX0_s1Z8oPqEeIFpaxlsnlYHbBOSqFoc1j9-gJ2baLHCUlyxIQZcjSzvwKCm-CtjyPJMC6h1FJ8R3xEP65nJC6niUwpgC1aJiYOZISYJm-RmM0mJ2PXgI-rB84EhCe7_aj6-fHDj9PPq_Ovn85OT85XtunqeTWAaJzqeiZFV3cDq1vTggLXDH3fMKE4WCPpoBh3ktVcQa8G2rvOgaU9gBBH1fut72bpJxgsxDmboDfZTyb_0cl4va9Ev9ZjutK8a1TH62LwcmeQ0-UCOOvJo4UQTIS0oG7bVtSykwV8fge8SEuJLKDmvG5bLgQt0IstNJoA2keXyqX22lGfcMbKJzSqLdTxf6iyBigxpgjOl_pew5u9hsLM8HsezYKoz75_22dfbVmbE2IGdxMGo_p6ZvRuZgr57N_sbrndkBTg9RbAIsUR8u2T73r9BYo8yqE</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>224662330</pqid></control><display><type>article</type><title>Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches</title><source>MEDLINE</source><source>SpringerLink Journals</source><source>Nature</source><creator>Chen, Mo ; Manley, James L.</creator><creatorcontrib>Chen, Mo ; Manley, James L.</creatorcontrib><description>Key Points
Alternative splicing is a crucial mechanism for gene regulation and for generating proteomic diversity, which allows individual genes to generate multiple mature mRNA isoforms that can be translated into functionally different proteins. Alternative splicing can be regulated at different stages of spliceosome assembly and by different mechanisms.
Splice site recognition of alternative exons is frequently regulated by cooperative interactions between factors such as SR (Ser–Arg) proteins and heterogeneous nuclear ribonucleoprotein particles (hnRNPs), which have lower affinities and sequence specificities. Splice site selection is also influenced by the secondary structure of mRNAs.
Two models have been proposed to explain the role of RNA polymerase II in alternative splicing regulation: a recruitment model and a kinetic model, and the two models are not mutually exclusive.
Alternative splicing, including tissue-specific alternative splicing, is an extremely common regulatory mechanism. However, the number of known sequence-specific alternative splicing factors (<50) is much smaller than that of sequence-specific transcription factors (∼2,500). Although more specific splicing factors will undoubtedly be discovered, this disparity suggests important differences in the pathways regulating transcription and splicing.
Core spliceosomal proteins can also regulate tissue-specific alternative splicing. This may reflect differential sensitivity of alternative exons to these factors and/or differential accumulation of the factors in different tissues.
Post-translational modifications of splicing factors enable cells to switch between alternative splicing isoforms rapidly after environmental stimuli. Phosphorylation can change the intracellular localization of splicing factor, protein–protein and protein–RNA interactions and even intrinsic splicing factor activity.
Alternative splicing is an important gene regulatory mechanism for generating proteomic diversity, which markedly affects human development and is misregulated in many human diseases. Alternative splicing can be regulated at different stages of spliceosome assembly and by different mechanisms.
Alternative splicing of mRNA precursors provides an important means of genetic control and is a crucial step in the expression of most genes. Alternative splicing markedly affects human development, and its misregulation underlies many human diseases. Although the mechanisms of alternative splicing have been studied extensively, until the past few years we had not begun to realize fully the diversity and complexity of alternative splicing regulation by an intricate protein–RNA network. Great progress has been made by studying individual transcripts and through genome-wide approaches, which together provide a better picture of the mechanistic regulation of alternative pre-mRNA splicing.</description><identifier>ISSN: 1471-0072</identifier><identifier>EISSN: 1471-0080</identifier><identifier>DOI: 10.1038/nrm2777</identifier><identifier>PMID: 19773805</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Alternative Splicing - genetics ; Antigens ; Biochemistry ; Biomedical and Life Sciences ; Cancer Research ; Cell Biology ; Developmental Biology ; Gene Expression Regulation ; Genetic regulation ; Genomics ; Humans ; Life Sciences ; Messenger RNA ; Physiological aspects ; Proteins ; review-article ; RNA Precursors - genetics ; RNA splicing ; Signal Transduction ; Stem Cells</subject><ispartof>Nature reviews. Molecular cell biology, 2009-11, Vol.10 (11), p.741-754</ispartof><rights>Springer Nature Limited 2009</rights><rights>COPYRIGHT 2009 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Nov 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c594t-de35f89b173949d146a6e8ef5dbb51382eca70d812f71428eb8d0bf9fec0bee33</citedby><cites>FETCH-LOGICAL-c594t-de35f89b173949d146a6e8ef5dbb51382eca70d812f71428eb8d0bf9fec0bee33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nrm2777$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nrm2777$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19773805$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Mo</creatorcontrib><creatorcontrib>Manley, James L.</creatorcontrib><title>Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches</title><title>Nature reviews. Molecular cell biology</title><addtitle>Nat Rev Mol Cell Biol</addtitle><addtitle>Nat Rev Mol Cell Biol</addtitle><description>Key Points
Alternative splicing is a crucial mechanism for gene regulation and for generating proteomic diversity, which allows individual genes to generate multiple mature mRNA isoforms that can be translated into functionally different proteins. Alternative splicing can be regulated at different stages of spliceosome assembly and by different mechanisms.
Splice site recognition of alternative exons is frequently regulated by cooperative interactions between factors such as SR (Ser–Arg) proteins and heterogeneous nuclear ribonucleoprotein particles (hnRNPs), which have lower affinities and sequence specificities. Splice site selection is also influenced by the secondary structure of mRNAs.
Two models have been proposed to explain the role of RNA polymerase II in alternative splicing regulation: a recruitment model and a kinetic model, and the two models are not mutually exclusive.
Alternative splicing, including tissue-specific alternative splicing, is an extremely common regulatory mechanism. However, the number of known sequence-specific alternative splicing factors (<50) is much smaller than that of sequence-specific transcription factors (∼2,500). Although more specific splicing factors will undoubtedly be discovered, this disparity suggests important differences in the pathways regulating transcription and splicing.
Core spliceosomal proteins can also regulate tissue-specific alternative splicing. This may reflect differential sensitivity of alternative exons to these factors and/or differential accumulation of the factors in different tissues.
Post-translational modifications of splicing factors enable cells to switch between alternative splicing isoforms rapidly after environmental stimuli. Phosphorylation can change the intracellular localization of splicing factor, protein–protein and protein–RNA interactions and even intrinsic splicing factor activity.
Alternative splicing is an important gene regulatory mechanism for generating proteomic diversity, which markedly affects human development and is misregulated in many human diseases. Alternative splicing can be regulated at different stages of spliceosome assembly and by different mechanisms.
Alternative splicing of mRNA precursors provides an important means of genetic control and is a crucial step in the expression of most genes. Alternative splicing markedly affects human development, and its misregulation underlies many human diseases. Although the mechanisms of alternative splicing have been studied extensively, until the past few years we had not begun to realize fully the diversity and complexity of alternative splicing regulation by an intricate protein–RNA network. Great progress has been made by studying individual transcripts and through genome-wide approaches, which together provide a better picture of the mechanistic regulation of alternative pre-mRNA splicing.</description><subject>Alternative Splicing - genetics</subject><subject>Antigens</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Developmental Biology</subject><subject>Gene Expression Regulation</subject><subject>Genetic regulation</subject><subject>Genomics</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Messenger RNA</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>review-article</subject><subject>RNA Precursors - genetics</subject><subject>RNA splicing</subject><subject>Signal Transduction</subject><subject>Stem Cells</subject><issn>1471-0072</issn><issn>1471-0080</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkltrFTEUhQdRbK3iP5Cg4OXh1FxmJhkfhFK8FCqCl1dDJrMzJyWTnGbPFP33ppxD6ymSh4S9vr1CVnZVPWX0mFGh3sY8cSnlveqQ1ZKtKFX0_s1Z8oPqEeIFpaxlsnlYHbBOSqFoc1j9-gJ2baLHCUlyxIQZcjSzvwKCm-CtjyPJMC6h1FJ8R3xEP65nJC6niUwpgC1aJiYOZISYJm-RmM0mJ2PXgI-rB84EhCe7_aj6-fHDj9PPq_Ovn85OT85XtunqeTWAaJzqeiZFV3cDq1vTggLXDH3fMKE4WCPpoBh3ktVcQa8G2rvOgaU9gBBH1fut72bpJxgsxDmboDfZTyb_0cl4va9Ev9ZjutK8a1TH62LwcmeQ0-UCOOvJo4UQTIS0oG7bVtSykwV8fge8SEuJLKDmvG5bLgQt0IstNJoA2keXyqX22lGfcMbKJzSqLdTxf6iyBigxpgjOl_pew5u9hsLM8HsezYKoz75_22dfbVmbE2IGdxMGo_p6ZvRuZgr57N_sbrndkBTg9RbAIsUR8u2T73r9BYo8yqE</recordid><startdate>20091101</startdate><enddate>20091101</enddate><creator>Chen, Mo</creator><creator>Manley, James L.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PCBAR</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20091101</creationdate><title>Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches</title><author>Chen, Mo ; Manley, James L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c594t-de35f89b173949d146a6e8ef5dbb51382eca70d812f71428eb8d0bf9fec0bee33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Alternative Splicing - genetics</topic><topic>Antigens</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cancer Research</topic><topic>Cell Biology</topic><topic>Developmental Biology</topic><topic>Gene Expression Regulation</topic><topic>Genetic regulation</topic><topic>Genomics</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Messenger RNA</topic><topic>Physiological aspects</topic><topic>Proteins</topic><topic>review-article</topic><topic>RNA Precursors - genetics</topic><topic>RNA splicing</topic><topic>Signal Transduction</topic><topic>Stem Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Mo</creatorcontrib><creatorcontrib>Manley, James L.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Earth, Atmospheric & Aquatic Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Earth, Atmospheric & Aquatic Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature reviews. Molecular cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Mo</au><au>Manley, James L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches</atitle><jtitle>Nature reviews. Molecular cell biology</jtitle><stitle>Nat Rev Mol Cell Biol</stitle><addtitle>Nat Rev Mol Cell Biol</addtitle><date>2009-11-01</date><risdate>2009</risdate><volume>10</volume><issue>11</issue><spage>741</spage><epage>754</epage><pages>741-754</pages><issn>1471-0072</issn><eissn>1471-0080</eissn><abstract>Key Points
Alternative splicing is a crucial mechanism for gene regulation and for generating proteomic diversity, which allows individual genes to generate multiple mature mRNA isoforms that can be translated into functionally different proteins. Alternative splicing can be regulated at different stages of spliceosome assembly and by different mechanisms.
Splice site recognition of alternative exons is frequently regulated by cooperative interactions between factors such as SR (Ser–Arg) proteins and heterogeneous nuclear ribonucleoprotein particles (hnRNPs), which have lower affinities and sequence specificities. Splice site selection is also influenced by the secondary structure of mRNAs.
Two models have been proposed to explain the role of RNA polymerase II in alternative splicing regulation: a recruitment model and a kinetic model, and the two models are not mutually exclusive.
Alternative splicing, including tissue-specific alternative splicing, is an extremely common regulatory mechanism. However, the number of known sequence-specific alternative splicing factors (<50) is much smaller than that of sequence-specific transcription factors (∼2,500). Although more specific splicing factors will undoubtedly be discovered, this disparity suggests important differences in the pathways regulating transcription and splicing.
Core spliceosomal proteins can also regulate tissue-specific alternative splicing. This may reflect differential sensitivity of alternative exons to these factors and/or differential accumulation of the factors in different tissues.
Post-translational modifications of splicing factors enable cells to switch between alternative splicing isoforms rapidly after environmental stimuli. Phosphorylation can change the intracellular localization of splicing factor, protein–protein and protein–RNA interactions and even intrinsic splicing factor activity.
Alternative splicing is an important gene regulatory mechanism for generating proteomic diversity, which markedly affects human development and is misregulated in many human diseases. Alternative splicing can be regulated at different stages of spliceosome assembly and by different mechanisms.
Alternative splicing of mRNA precursors provides an important means of genetic control and is a crucial step in the expression of most genes. Alternative splicing markedly affects human development, and its misregulation underlies many human diseases. Although the mechanisms of alternative splicing have been studied extensively, until the past few years we had not begun to realize fully the diversity and complexity of alternative splicing regulation by an intricate protein–RNA network. Great progress has been made by studying individual transcripts and through genome-wide approaches, which together provide a better picture of the mechanistic regulation of alternative pre-mRNA splicing.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>19773805</pmid><doi>10.1038/nrm2777</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alternative Splicing - genetics Antigens Biochemistry Biomedical and Life Sciences Cancer Research Cell Biology Developmental Biology Gene Expression Regulation Genetic regulation Genomics Humans Life Sciences Messenger RNA Physiological aspects Proteins review-article RNA Precursors - genetics RNA splicing Signal Transduction Stem Cells |
| title | Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches |
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