An<i>NXF1</i>mRNA with a retained intron is expressed in hippocampal and neocortical neurons and is translated into a protein that functions as an Nxf1 cofactor

Li, Ying; Bor, Yeou-Cherng; Fitzgerald, Mark P.; Lee, Kevin M.; Rekosh, David; Hammarskjöld, Marie‐Louise

doi:10.1091/mbc.e16-07-0515

Cited by 32 publications

(33 citation statements)

References 74 publications

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“…This allows for the NXF1 IR isoform to be transported to the cytosol and translated into a C-terminal truncated sNXF1 protein that serves as a cofactor to its full-length counterpart. sNXF1 has recently been shown to be expressed in hippocampal and cortical neurons, localizing in cytoplasmic granules suggestive of functionality in the cytosolic export of the other intron containing mRNA (Li et al 2016 ).…”

Section: Protein-coding Irmentioning

confidence: 99%

Intron retention as a component of regulated gene expression programs

2017

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Intron retention has long been an exemplar of regulated splicing with case studies of individual events serving as models that provided key mechanistic insights into the process of splicing control. In organisms such as plants and budding yeast, intron retention is well understood as a major mechanism of gene expression regulation. In contrast, in mammalian systems, the extent and functional significance of intron retention have, until recently, remained greatly underappreciated. Technical challenges to the global detection and quantitation of transcripts with retained introns have often led to intron retention being overlooked or dismissed as “noise”. Now, however, with the wealth of information available from high-throughput deep sequencing, combined with focused computational and statistical analyses, we are able to distinguish clear intron retention patterns in various physiological and pathological contexts. Several recent studies have demonstrated intron retention as a central component of gene expression programs during normal development as well as in response to stress and disease. Furthermore, these studies revealed various ways in which intron retention regulates protein isoform production, RNA stability and translation efficiency, and rapid induction of expression via post-transcriptional splicing of retained introns. In this review, we highlight critical findings from these transcriptomic studies and discuss commonalties in the patterns prevalent in intron retention networks at the functional and regulatory levels.

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Section: Protein-coding Irmentioning

confidence: 99%

Intron retention as a component of regulated gene expression programs

2017

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“…Partial diversion of transcriptional output into IR isoforms also functions as a post-transcriptional pathway to modulate expression levels (Wong et al 2013;Braunschweig et al 2014;Shalgi et al 2014;Boutz et al 2015;Ni et al 2016). Some IR transcripts can be recruited to ribosomes to function in translation (Li et al 2016), while others might serve as miRNA sponges in the nucleus (Schmitz et al 2017).…”

Section: Introductionmentioning

confidence: 99%

An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys

Parra

Booth

Weiszmann

et al. 2018

RNA

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During terminal erythropoiesis, the splicing machinery in differentiating erythroblasts executes a robust intron retention (IR) program that impacts expression of hundreds of genes. We studied IR mechanisms in the splicing factor gene, which expresses ∼50% of its transcripts in late erythroblasts as a nuclear isoform that retains intron 4. RNA-seq analysis of nonsense-mediated decay (NMD)-inhibited cells revealed previously undescribed splice junctions, rare or not detected in normal cells, that connect constitutive exons 4 and 5 to highly conserved cryptic cassette exons within the intron. Minigene splicing reporter assays showed that these cassettes promote IR. Genome-wide analysis of splice junction reads demonstrated that cryptic noncoding cassettes are much more common in large (>1 kb) retained introns than they are in small retained introns or in nonretained introns. Functional assays showed that heterologous cassettes can promote retention of intron 4 in the splicing reporter. Although many of these cryptic exons were spliced inefficiently, they exhibited substantial binding of U2AF1 and U2AF2 adjacent to their splice acceptor sites. We propose that these exons function as decoys that engage the intron-terminal splice sites, thereby blocking cross-intron interactions required for excision. Developmental regulation of decoy function underlies a major component of the erythroblast IR program.

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“…Partial diversion of transcriptional output into IR isoforms also functions as a post-transcriptional pathway to modulate expression levels (Wong et al 2013; Braunschweig et al 2014; Shalgi et al 2014; Boutz et al 2015; Ni et al 2016). Some IR transcripts can be recruited to ribosomes to function in translation (Li et al 2016), while other might serve as miRNA sponges in the nucleus (Schmitz et al 2017).…”

Section: Introductionmentioning

confidence: 99%

An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys

Parra¹,

Booth²,

Weiszmann³

et al. 2018

Preprint

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During terminal erythropoiesis, the splicing machinery in differentiating erythroblasts executes a robust intron retention (IR) program that impacts expression of hundreds of genes. We studied IR mechanisms in the SF3B1 splicing factor gene, which expresses ∼50% of its transcripts in late erythroblasts as a nuclear isoform that retains intron 4. RNA-seq analysis of nonsense-mediated decay (NMD)-inhibited cells revealed splice junctions connecting constitutive exons 4 and 5 to cryptic cassette exons encoded in highly conserved intron sequences. In minigene splicing reporter assays, these cassette exons functioned to promote IR. Genome-wide analysis of splice junction reads demonstrated that cryptic noncoding cassettes are much more common in large (>1kb) retained introns than they are in small retained introns or in non-retained introns. Functional assays showed that heterologous cassettes could promote retention of intron 4 in the SF3B1 splicing reporter. Although most of these cryptic exons were spliced inefficiently, they exhibited substantial binding of U2AF1 and U2AF2 adjacent to their splice acceptor sites. We propose that these exons function as decoys that engage the intron-terminal splice sites, blocking cross-intron interactions required for excision. Developmental regulation of decoy function underlies a major component of the erythroblast IR program.

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AnNXF1mRNA with a retained intron is expressed in hippocampal and neocortical neurons and is translated into a protein that functions as an Nxf1 cofactor

Cited by 32 publications

References 74 publications

Intron retention as a component of regulated gene expression programs

Intron retention as a component of regulated gene expression programs

An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys

An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys

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