Unusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins

We identify a type of polycistronic transcript-derived long noncoding RNAs (lncRNAs) that are 5′ small nucleolar RNA (snoRNA) capped and 3′ polyadenylated (SPAs). SPA processing is associated with nascent mRNA 3′ processing and kinetic competition between XRN2 trimming and Pol II elongation. Followi...

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Veröffentlicht in:Molecular cell 2016-11, Vol.64 (3), p.534-548
Hauptverfasser: Wu, Huang, Yin, Qing-Fei, Luo, Zheng, Yao, Run-Wen, Zheng, Chuan-Chuan, Zhang, Jun, Xiang, Jian-Feng, Yang, Li, Chen, Ling-Ling
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container_end_page 548
container_issue 3
container_start_page 534
container_title Molecular cell
container_volume 64
creator Wu, Huang
Yin, Qing-Fei
Luo, Zheng
Yao, Run-Wen
Zheng, Chuan-Chuan
Zhang, Jun
Xiang, Jian-Feng
Yang, Li
Chen, Ling-Ling
description We identify a type of polycistronic transcript-derived long noncoding RNAs (lncRNAs) that are 5′ small nucleolar RNA (snoRNA) capped and 3′ polyadenylated (SPAs). SPA processing is associated with nascent mRNA 3′ processing and kinetic competition between XRN2 trimming and Pol II elongation. Following cleavage/polyadenylation of its upstream gene, the downstream uncapped pre-SPA is trimmed by XRN2 until this exonuclease reaches the co-transcriptionally assembled snoRNP. This snoRNP complex prevents further degradation, generates a snoRNA 5′ end, and allows continuous Pol II elongation. The imprinted 15q11-q13 encodes two SPAs that are deleted in Prader-Willi syndrome (PWS) patients. These lncRNAs form a nuclear accumulation that is enriched in RNA binding proteins (RBPs) including TDP43, RBFOX2, and hnRNP M. Generation of a human PWS cellular model by depleting these lncRNAs results in altered patterns of RBPs binding and alternative splicing. Together, these results expand the diversity of lncRNAs and provide additional insights into PWS pathogenesis. [Display omitted] •Unusual processing generates 5′ SnoRNA capped and 3′ PolyAdenylated (SPA) lncRNAs•SPA processing requires a fast Pol II and snoRNP protection from XRN2 trimming•Two SPAs that sequester multiple RBPs in hESCs are absent in PWS patients•Knockout SPAs in hESCs leads to altered patterns of RBPs binding and splicing Wu et al. report SPA lncRNAs that are capped by snoRNAs and require snoRNP complexes to protect them from trimming by XRN2. Two SPAs associated with Prader-Willi syndrome can sequester multiple RBPs and regulate alternative splicing.
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SPA processing is associated with nascent mRNA 3′ processing and kinetic competition between XRN2 trimming and Pol II elongation. Following cleavage/polyadenylation of its upstream gene, the downstream uncapped pre-SPA is trimmed by XRN2 until this exonuclease reaches the co-transcriptionally assembled snoRNP. This snoRNP complex prevents further degradation, generates a snoRNA 5′ end, and allows continuous Pol II elongation. The imprinted 15q11-q13 encodes two SPAs that are deleted in Prader-Willi syndrome (PWS) patients. These lncRNAs form a nuclear accumulation that is enriched in RNA binding proteins (RBPs) including TDP43, RBFOX2, and hnRNP M. Generation of a human PWS cellular model by depleting these lncRNAs results in altered patterns of RBPs binding and alternative splicing. Together, these results expand the diversity of lncRNAs and provide additional insights into PWS pathogenesis. [Display omitted] •Unusual processing generates 5′ SnoRNA capped and 3′ PolyAdenylated (SPA) lncRNAs•SPA processing requires a fast Pol II and snoRNP protection from XRN2 trimming•Two SPAs that sequester multiple RBPs in hESCs are absent in PWS patients•Knockout SPAs in hESCs leads to altered patterns of RBPs binding and splicing Wu et al. report SPA lncRNAs that are capped by snoRNAs and require snoRNP complexes to protect them from trimming by XRN2. Two SPAs associated with Prader-Willi syndrome can sequester multiple RBPs and regulate alternative splicing.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2016.10.007</identifier><identifier>PMID: 27871485</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alternative Splicing ; Base Sequence ; Chromosomes, Human, Pair 15 ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Exoribonucleases - genetics ; Exoribonucleases - metabolism ; Genetic Loci ; Genomic Imprinting ; Heterogeneous-Nuclear Ribonucleoprotein Group M - genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group M - metabolism ; Human Embryonic Stem Cells - metabolism ; Human Embryonic Stem Cells - pathology ; Humans ; Prader-Willi Syndrome - genetics ; Prader-Willi Syndrome - metabolism ; Prader-Willi Syndrome - pathology ; Protein Binding ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; RNA Polymerase II - genetics ; RNA Polymerase II - metabolism ; RNA Splicing Factors - genetics ; RNA Splicing Factors - metabolism ; RNA, Long Noncoding - genetics ; RNA, Long Noncoding - metabolism ; RNA, Small Nucleolar - genetics ; RNA, Small Nucleolar - metabolism ; Sequence Deletion ; Transcription, Genetic</subject><ispartof>Molecular cell, 2016-11, Vol.64 (3), p.534-548</ispartof><rights>2016 Elsevier Inc.</rights><rights>Copyright © 2016 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-8ebc56b939231833234293ec820c810a4890db20700051516b37ac77cbee120b3</citedby><cites>FETCH-LOGICAL-c408t-8ebc56b939231833234293ec820c810a4890db20700051516b37ac77cbee120b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S109727651630630X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27871485$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Huang</creatorcontrib><creatorcontrib>Yin, Qing-Fei</creatorcontrib><creatorcontrib>Luo, Zheng</creatorcontrib><creatorcontrib>Yao, Run-Wen</creatorcontrib><creatorcontrib>Zheng, Chuan-Chuan</creatorcontrib><creatorcontrib>Zhang, Jun</creatorcontrib><creatorcontrib>Xiang, Jian-Feng</creatorcontrib><creatorcontrib>Yang, Li</creatorcontrib><creatorcontrib>Chen, Ling-Ling</creatorcontrib><title>Unusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>We identify a type of polycistronic transcript-derived long noncoding RNAs (lncRNAs) that are 5′ small nucleolar RNA (snoRNA) capped and 3′ polyadenylated (SPAs). SPA processing is associated with nascent mRNA 3′ processing and kinetic competition between XRN2 trimming and Pol II elongation. Following cleavage/polyadenylation of its upstream gene, the downstream uncapped pre-SPA is trimmed by XRN2 until this exonuclease reaches the co-transcriptionally assembled snoRNP. This snoRNP complex prevents further degradation, generates a snoRNA 5′ end, and allows continuous Pol II elongation. The imprinted 15q11-q13 encodes two SPAs that are deleted in Prader-Willi syndrome (PWS) patients. These lncRNAs form a nuclear accumulation that is enriched in RNA binding proteins (RBPs) including TDP43, RBFOX2, and hnRNP M. Generation of a human PWS cellular model by depleting these lncRNAs results in altered patterns of RBPs binding and alternative splicing. Together, these results expand the diversity of lncRNAs and provide additional insights into PWS pathogenesis. [Display omitted] •Unusual processing generates 5′ SnoRNA capped and 3′ PolyAdenylated (SPA) lncRNAs•SPA processing requires a fast Pol II and snoRNP protection from XRN2 trimming•Two SPAs that sequester multiple RBPs in hESCs are absent in PWS patients•Knockout SPAs in hESCs leads to altered patterns of RBPs binding and splicing Wu et al. report SPA lncRNAs that are capped by snoRNAs and require snoRNP complexes to protect them from trimming by XRN2. Two SPAs associated with Prader-Willi syndrome can sequester multiple RBPs and regulate alternative splicing.</description><subject>Alternative Splicing</subject><subject>Base Sequence</subject><subject>Chromosomes, Human, Pair 15</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Exoribonucleases - genetics</subject><subject>Exoribonucleases - metabolism</subject><subject>Genetic Loci</subject><subject>Genomic Imprinting</subject><subject>Heterogeneous-Nuclear Ribonucleoprotein Group M - genetics</subject><subject>Heterogeneous-Nuclear Ribonucleoprotein Group M - metabolism</subject><subject>Human Embryonic Stem Cells - metabolism</subject><subject>Human Embryonic Stem Cells - pathology</subject><subject>Humans</subject><subject>Prader-Willi Syndrome - genetics</subject><subject>Prader-Willi Syndrome - metabolism</subject><subject>Prader-Willi Syndrome - pathology</subject><subject>Protein Binding</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>RNA Polymerase II - genetics</subject><subject>RNA Polymerase II - metabolism</subject><subject>RNA Splicing Factors - genetics</subject><subject>RNA Splicing Factors - metabolism</subject><subject>RNA, Long Noncoding - genetics</subject><subject>RNA, Long Noncoding - metabolism</subject><subject>RNA, Small Nucleolar - genetics</subject><subject>RNA, Small Nucleolar - metabolism</subject><subject>Sequence Deletion</subject><subject>Transcription, Genetic</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EoqXwBwh5ySZl7Dixs0EqFRSkAhWlaytxpuAqTYqdIPH3uLSwZDWe8b3zOIScMxgyYOnVarhuKoPVkIcslIYA8oD0GWQyEiwVh_s3l2nSIyferwCYSFR2THpcKsmESvpksag73-UVnbnGoPe2fqMTrNHlLXo6n43otDYvTyNP2_e8pXP86NC36OhjV7V2UyENn_TG1uXWGZq0aGt_So6WeeXxbB8HZHF3-zq-j6bPk4fxaBoZAaqNFBYmSYssznjMVBzzWPAsRqM4GMUgFyqDsuAgASBhCUuLWOZGSlMgMg5FPCCXu74b1_wsptfWByZVXmPTec2U4EmWhcODVOykxjXeO1zqjbPr3H1pBnoLVK_0DqjeAt1WA9Bgu9hP6Io1ln-mX4JBcL0TYLjz06LT3lisDZbWoWl12dj_J3wDEpGG9A</recordid><startdate>20161103</startdate><enddate>20161103</enddate><creator>Wu, Huang</creator><creator>Yin, Qing-Fei</creator><creator>Luo, Zheng</creator><creator>Yao, Run-Wen</creator><creator>Zheng, Chuan-Chuan</creator><creator>Zhang, Jun</creator><creator>Xiang, Jian-Feng</creator><creator>Yang, Li</creator><creator>Chen, Ling-Ling</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope></search><sort><creationdate>20161103</creationdate><title>Unusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins</title><author>Wu, Huang ; 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SPA processing is associated with nascent mRNA 3′ processing and kinetic competition between XRN2 trimming and Pol II elongation. Following cleavage/polyadenylation of its upstream gene, the downstream uncapped pre-SPA is trimmed by XRN2 until this exonuclease reaches the co-transcriptionally assembled snoRNP. This snoRNP complex prevents further degradation, generates a snoRNA 5′ end, and allows continuous Pol II elongation. The imprinted 15q11-q13 encodes two SPAs that are deleted in Prader-Willi syndrome (PWS) patients. These lncRNAs form a nuclear accumulation that is enriched in RNA binding proteins (RBPs) including TDP43, RBFOX2, and hnRNP M. Generation of a human PWS cellular model by depleting these lncRNAs results in altered patterns of RBPs binding and alternative splicing. Together, these results expand the diversity of lncRNAs and provide additional insights into PWS pathogenesis. [Display omitted] •Unusual processing generates 5′ SnoRNA capped and 3′ PolyAdenylated (SPA) lncRNAs•SPA processing requires a fast Pol II and snoRNP protection from XRN2 trimming•Two SPAs that sequester multiple RBPs in hESCs are absent in PWS patients•Knockout SPAs in hESCs leads to altered patterns of RBPs binding and splicing Wu et al. report SPA lncRNAs that are capped by snoRNAs and require snoRNP complexes to protect them from trimming by XRN2. Two SPAs associated with Prader-Willi syndrome can sequester multiple RBPs and regulate alternative splicing.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27871485</pmid><doi>10.1016/j.molcel.2016.10.007</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record>
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subjects Alternative Splicing
Base Sequence
Chromosomes, Human, Pair 15
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Exoribonucleases - genetics
Exoribonucleases - metabolism
Genetic Loci
Genomic Imprinting
Heterogeneous-Nuclear Ribonucleoprotein Group M - genetics
Heterogeneous-Nuclear Ribonucleoprotein Group M - metabolism
Human Embryonic Stem Cells - metabolism
Human Embryonic Stem Cells - pathology
Humans
Prader-Willi Syndrome - genetics
Prader-Willi Syndrome - metabolism
Prader-Willi Syndrome - pathology
Protein Binding
Repressor Proteins - genetics
Repressor Proteins - metabolism
RNA Polymerase II - genetics
RNA Polymerase II - metabolism
RNA Splicing Factors - genetics
RNA Splicing Factors - metabolism
RNA, Long Noncoding - genetics
RNA, Long Noncoding - metabolism
RNA, Small Nucleolar - genetics
RNA, Small Nucleolar - metabolism
Sequence Deletion
Transcription, Genetic
title Unusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins
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