title: Unusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins.
abstract: 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.
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Huang
authors.initials: H
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Qing-Fei
authors.initials: QF
authors.lastname: Yin
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Run-Wen
authors.initials: RW
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Chuan-Chuan
authors.initials: CC
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Computational Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Xiang
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science, ShanghaiTech University, Shanghai 200031, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science, ShanghaiTech University, Shanghai 200031, China. Electronic address: linglingchen@sibcb.ac.cn.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Chen
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D002884:Chromosomes, Human, Pair 15; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005095:Exoribonucleases / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci; D018392:Genomic Imprinting; D034761:Heterogeneous-Nuclear Ribonucleoprotein Group M / Q000235:genetics / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D020537:RNA, Small Nucleolar / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D034761:Heterogeneous-Nuclear Ribonucleoprotein Group M; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D062085:RNA, Long Noncoding; D020537:RNA, Small Nucleolar; D012097:Repressor Proteins; C000598624:TARDBP protein, human; D012319:RNA Polymerase II; D005095:Exoribonucleases; C120903:XRN2 protein, human