U1 snRNP regulates chromatin retention of noncoding RNAs

Yafei Yin (), J. Yuyang Lu, Xuechun Zhang, Wen Shao, Yanhui Xu, Pan Li, Yantao Hong, Li Cui, Ge Shan, Bin Tian, Qiangfeng Cliff Zhang and Xiaohua Shen ()
Additional contact information
Yafei Yin: Tsinghua University
J. Yuyang Lu: Tsinghua University
Xuechun Zhang: Tsinghua University
Wen Shao: Tsinghua University
Yanhui Xu: Tsinghua University
Pan Li: Tsinghua University
Yantao Hong: Tsinghua University
Li Cui: Tsinghua University
Ge Shan: University of Science and Technology of China
Bin Tian: Rutgers New Jersey Medical School and Rutgers Cancer Institute of New Jersey
Qiangfeng Cliff Zhang: Tsinghua University
Xiaohua Shen: Tsinghua University

Nature, 2020, vol. 580, issue 7801, 147-150

Abstract: Abstract Long noncoding RNAs (lncRNAs) and promoter- or enhancer-associated unstable transcripts locate preferentially to chromatin, where some regulate chromatin structure, transcription and RNA processing1–13. Although several RNA sequences responsible for nuclear localization have been identified—such as repeats in the lncRNA Xist and Alu-like elements in long RNAs14–16—how lncRNAs as a class are enriched at chromatin remains unknown. Here we describe a random, mutagenesis-coupled, high-throughput method that we name ‘RNA elements for subcellular localization by sequencing’ (mutREL-seq). Using this method, we discovered an RNA motif that recognizes the U1 small nuclear ribonucleoprotein (snRNP) and is essential for the localization of reporter RNAs to chromatin. Across the genome, chromatin-bound lncRNAs are enriched with 5′ splice sites and depleted of 3′ splice sites, and exhibit high levels of U1 snRNA binding compared with cytoplasm-localized messenger RNAs. Acute depletion of U1 snRNA or of the U1 snRNP protein component SNRNP70 markedly reduces the chromatin association of hundreds of lncRNAs and unstable transcripts, without altering the overall transcription rate in cells. In addition, rapid degradation of SNRNP70 reduces the localization of both nascent and polyadenylated lncRNA transcripts to chromatin, and disrupts the nuclear and genome-wide localization of the lncRNA Malat1. Moreover, U1 snRNP interacts with transcriptionally engaged RNA polymerase II. These results show that U1 snRNP acts widely to tether and mobilize lncRNAs to chromatin in a transcription-dependent manner. Our findings have uncovered a previously unknown role of U1 snRNP beyond the processing of precursor mRNA, and provide molecular insight into how lncRNAs are recruited to regulatory sites to carry out chromatin-associated functions.

Date: 2020
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DOI: 10.1038/s41586-020-2105-3

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