Evolutionarily conserved autoregulation of alternative pre-mRNA splicing by ribosomal protein L10a

Takei, Satomi; Togo-Ohno, Marina; Suzuki, Yutaka; Kuroyanagi, Hidehito

doi:10.1093/nar/gkw152

Cited by 25 publications

(39 citation statements)

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“…A number of studies have reported negative feedback mechanisms in which protein levels are autoregulated by modulating alternative mRNA splicing followed by NMD (22,27–31), but the molecular mechanisms underlying such autoregulation have been elucidated for only a few proteins (15–17,31). One such case is PTB, for which a high concentration increases its binding to intron 10 of its mRNA; this increases exon 11 skipping, producing an mRNA that then undergoes NMD (16).…”

Section: Discussionmentioning

confidence: 99%

Chtop (Chromatin target of Prmt1) auto-regulates its expression level via intron retention and nonsense-mediated decay of its own mRNA

et al. 2016

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Chtop (chromatin target of Prmt1) regulates various aspects of gene expression including transcription and mRNA export. Despite these important functions, the regulatory mechanism underlying Chtop expression remains undetermined. Using Chtop-expressing human cell lines, we demonstrate that Chtop expression is controlled via an autoregulatory negative feedback loop whereby Chtop binds its own mRNA to retain intron 2 during splicing; a premature termination codon present at the 5′ end of intron 2 leads to nonsense-mediated decay of the mRNA. We also show that Chtop interacts with exon 2 of Chtop mRNA via its arginine-glycine-rich (RG) domain, and with intron 2 via its N-terminal (N1) domain; both are required for retention of intron 2. In addition, we show that hnRNP H accelerates intron 2 splicing of Chtop mRNA in a manner dependent on Chtop expression level, suggesting that Chtop and hnRNP H regulate intron 2 retention of Chtop mRNA antagonistically. Thus, the present study provides a novel molecular mechanism by which mRNA and protein levels are constitutively regulated by intron retention.

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Section: Discussionmentioning

confidence: 99%

Chtop (Chromatin target of Prmt1) auto-regulates its expression level via intron retention and nonsense-mediated decay of its own mRNA

et al. 2016

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“…Fluorescence splicing reporters for the rpl‐1 gene, encoding L10a, revealed that the alternative splicing regulation occurs uniformly throughout the body. A short stretch of approximately 40 nucleotides between the two competitive 5′ splice sites, termed L10a regulatory element (L10ARE), is evolutionarily conserved in the orthologous introns of the L10a‐encoding genes . Splicing reporter‐based analyses demonstrated that L10ARE is necessary for splicing autoregulation by L10a in both C .…”

Section: Excellent Model For Pre‐mrna Processing In Vivomentioning

confidence: 99%

An emerging model organism Caenorhabditis elegans for alternative pre‐mRNA processing in vivo

Wani

Kuroyanagi

2017

WIREs RNA

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A nematode Caenorhabditis elegans is an intron-rich organism and up to 25% of its pre-mRNAs are estimated to be alternatively processed. Its compact genomic organization enables construction of fluorescence splicing reporters with intact genomic sequences and visualization of alternative processing patterns of interest in the transparent living animals with single-cell resolution. Genetic analysis with the reporter worms facilitated identification of trans-acting factors and cis-acting elements, which are highly conserved in mammals. Analysis of unspliced and partially spliced pre-mRNAs in vivo raised models for alternative splicing regulation relying on specific order of intron excision. RNA-seq analysis of splicing factor mutants and CLIP-seq analysis of the factors allow global search for target genes in the whole animal. An mRNA surveillance system is not essential for its viability or fertility, allowing analysis of unproductively spliced noncoding mRNAs. These features offer C. elegans as an ideal model organism for elucidating alternative pre-mRNA processing mechanisms in vivo. Examples of isoform-specific functions of alternatively processed genes are summarized. WIREs RNA 2017, 8:e1428. doi: 10.1002/wrna.1428 For further resources related to this article, please visit the WIREs website.

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“…Studies in Caenorhabditis elegans have shown that it is not uncommon 332 among ribosomal proteins to be AS-NMD targets [25]. In particular, ribosomal proteins L3, L10a, and 333 L12 use an evolutionarily-conserved pathway to insert PTCs in their pre-mRNA [76][77][78]. Here we show 334 that exon 2 of RPS3 has an alternative upstream donor site that induces a frameshift and targets RPS3 335 pre-mRNA for degradation ( Figure 4c).…”

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confidence: 73%

“…Consistently with this, exon 2 338 of RPS3 pre-mRNA contains a cognate eCLIP peak of RPS3, suggesting autoregulatory negative feedback 339 loop with a poison 5'-splice site in this gene. Remarkably, the ribosomal protein L10a in Caenorhabditis 340 elegans uses exactly the same strategy of regulation by specifically switching the donor site of its intron 3 to 341 create an unproductively spliced mRNA [78].…”

mentioning

confidence: 99%

“…A case that is reciprocal to poison exons, termed here as "essential" exon, 77 occurs when a cassette exon, which is normally included in the mature mRNA, triggers NMD when skipped. 78 For instance, alternative skipping of PTB exon 11 yields an mRNA that is removed by NMD, and the 79 2/22 skipping is itself promoted by PTB in a negative feedback loop [36]. Similarly, the spliceosomal RNA 80 binding protein RBM10, which is associated with TARP syndrome and lung adenocarcinoma, downregulates 81 its own expression and that of RBM5 by promoting skipping of several its essential exons [39].…”

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Novel autoregulatory cases of alternative splicing coupled with nonsense-mediated mRNA decay

Pervouchine

Popov

Berry

et al. 2018

Preprint

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Nonsense-mediated decay (NMD) is a eukaryotic mRNA surveillance system that selectively degrades 1 transcripts with premature termination codons (PTC). Many RNA-binding proteins (RBP) regulate their 2 expression levels by a negative feedback loop, in which RBP binds its own pre-mRNA and causes alternative 3 splicing to introduce a PTC. We present a bioinformatic framework to identify novel such autoregulatory 4 feedback loops by combining eCLIP assays for a large panel of RBPs with the data on shRNA inactivation 5 of NMD pathway, and shRNA-depletion of RBPs followed by RNA-seq. We show that RBPs frequently bind 6 their own pre-mRNAs and respond prominently to NMD pathway disruption. Poison and essential exons, 7 i.e., exons that trigger NMD when included in the mRNA or skipped, respectively, respond oppositely to the 8 inactivation of NMD pathway and to the depletion of their host genes, which allows identification of novel 9 autoregulatory mechanisms for a number of human RBPs. For example, SRSF7 binds its own pre-mRNA 10 and facilitates the inclusion of two poison exons; SFPQ binding promotes switching to an alternative distal 11 3'-UTR that is targeted by NMD; RPS3 activates a poison 5'-splice site in its pre-mRNA that leads to a 12 frame shift; U2AF1 binding activates one of its two mutually exclusive exons, leading to NMD; TBRG4 is 13 regulated by cluster splicing of its two essential exons. Our results indicate that autoregulatory negative 14 feedback loop of alternative splicing and NMD is a generic form of post-transcriptional control of gene 15 expression. 16Introduction 17 Gene expression in higher eukaryotes is regulated at many different levels. The output of the transcriptional 18 program is maintained by a large number of protein factors and cis-regulatory elements, which control 19 the balance between mRNA production and degradation [1,2]. Nonsense mutations and frame-shifting 20 splicing errors induce premature termination codons (PTC) that give rise to mRNAs encoding truncated, 21 dysfunctional proteins. In eukaryotic cells, mRNA transcripts with PTC are selectively degraded by the 22 surveillance mechanism called Nonsense-Mediated mRNA Decay (NMD) [3]. 23The so-called exon junction complex-dependent (EJC) model postulates that NMD distinguishes between 24 normal and premature translation termination in the cytoplasm, where ribosomes displace EJCs from within, 25 but not downstream of the reading frame [4,5]. These complexes are deposited approximately 50 nucleotides 26 (nt) upstream of the exon-exon junctions during pre-mRNA splicing. EJCs that remain associated with 27Short-hairpin RNA knockdown of RBP followed by RNA-seq 131 Publicly available data on short-hairpin (shRNA) knockdown of 250 RBPs followed by RNA-seq (shRNA-132 KD) [51] were downloaded in BAM format from ENCODE data repository [52,53]. A summary of RBP 133 depletion data and the respective accession numbers is given in Supplementary Table S1. Exon inclusion 134 metrics (PSI) were called for all annotated exons using IPSA software...

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Evolutionarily conserved autoregulation of alternative pre-mRNA splicing by ribosomal protein L10a

Cited by 25 publications

References 73 publications

Chtop (Chromatin target of Prmt1) auto-regulates its expression level via intron retention and nonsense-mediated decay of its own mRNA

Chtop (Chromatin target of Prmt1) auto-regulates its expression level via intron retention and nonsense-mediated decay of its own mRNA

An emerging model organism Caenorhabditis elegans for alternative pre‐mRNA processing in vivo

Novel autoregulatory cases of alternative splicing coupled with nonsense-mediated mRNA decay

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