Unusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins

Huang Wu; Qing-Fei Yin; Zheng Luo; Run-Wen Yao; Chuan-Chuan Zheng; Jun Zhang; Jian-Feng Xiang; Li Yang; Ling-Ling Chen

doi:10.1016/j.molcel.2016.10.007

Unusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins

Mol Cell. 2016 Nov 3;64(3):534-548. doi: 10.1016/j.molcel.2016.10.007. Epub 2016 Oct 27.

Authors

Huang Wu¹, Qing-Fei Yin², Zheng Luo³, Run-Wen Yao¹, Chuan-Chuan Zheng¹, Jun Zhang², Jian-Feng Xiang⁴, Li Yang⁵, Ling-Ling Chen⁶

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 27871485
DOI: 10.1016/j.molcel.2016.10.007

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.

MeSH terms

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
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
Repressor Proteins / genetics
Repressor Proteins / metabolism
Sequence Deletion*
Transcription, Genetic*

Substances

DNA-Binding Proteins
Heterogeneous-Nuclear Ribonucleoprotein Group M
RBFOX2 protein, human
RNA Splicing Factors
RNA, Long Noncoding
RNA, Small Nucleolar
Repressor Proteins
TARDBP protein, human
RNA Polymerase II
Exoribonucleases
XRN2 protein, human