ELAV and FNE Determine Neuronal Transcript Signatures through EXon-Activated Rescue

Carrasco, Judit; Rauer, Michael; Hummel, Barbara; Grzejda, Dominika; Alfonso-Gonzalez, Carlos; Lee, Yeon; Wang, Qingqing; Puchalska, Monika; Mittler, Gerhard; Hilgers, Valérie

doi:10.1016/j.molcel.2020.09.011

Cited by 37 publications

(146 citation statements)

References 75 publications

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“…Fourth, the functional overlap of Elav and Fne involves a regulatory interplay, because Elav represses fne alternative splicing that switches it from a cytoplasmic to a nuclear isoform. The hierarchical role of Elav and Fne in neural mRNA processing was also reported in a contemporary study by the Hilgers group [45].…”

Section: Introductionsupporting

confidence: 61%

“…A comprehensive summary of de novo motif searches are presented in S6 Fig. We obtained similar, but more exaggerated results, when we directly compared introns flanking excluded exons and included exons for differential motifs (S6 Fig) . Visual inspection of upstream introns of the validated ELAV/Hu splicing targets confirm that introns flanking newly validated exon exclusion targets, such as Medea and Axin, and the recently recognition that Fne is an exquisitely sensitive exon exclusion target of Elav [44,45], tend to have far more matches to Elav consensus motifs in flanking introns than the newly validated exon inclusion targets (Fig 3G). Interestingly, the previously known exclusion target arm was the only validated targed that lacked a preponderence of consensus Elav consensus motifs, although it had other U-rich regions (Fig 3G).…”

Section: Plos Geneticsmentioning

confidence: 60%

“…These loci harbor exons that are included in control S2 cells or cells expressing 3xRRM-mutant versions of Elav/Fne/Rbp9, but are efficiently skipped in cells expressing wildtype Elav/Fne/Rbp9 (Figs 2I and S2). On the other hand, their exons are skipped in wt and elav [5] L1-CNS, but are included in elav [5] While this work was under consideration, Hilgers and colleagues reported that elav mutant embryos exhibited splicing defects that were exacerbated by concurrent deletion of fne [45]. While these conclusions appear in line with ours, their annotations used RNA-seq data from whole embryos, which are confounded by expression of non-neuronal isoforms layered on top of potentially altered mRNA processing in ELAV/Hu-mutant nervous system.…”

Section: Plos Geneticsmentioning

confidence: 98%

“…While this study was under review, Hilgers and colleagues also reported that elav/fne double mutant embryo RNA-seq data showed defects in the expression of a set of neural alternative last exons [45]. For reasons described above, whole embryo data are under-powered to determine these isoform changes.…”

Section: Hierarchical Activities Of Elav/hu Factors Also Drive Globalmentioning

confidence: 98%

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ELAV/Hu RNA binding proteins determine multiple programs of neural alternative splicing

Lee

Zhang

et al. 2021

PLoS Genet

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ELAV/Hu factors are conserved RNA binding proteins (RBPs) that play diverse roles in mRNA processing and regulation. The founding member, Drosophila Elav, was recognized as a vital neural factor 35 years ago. Nevertheless, little was known about its impacts on the transcriptome, and potential functional overlap with its paralogs. Building on our recent findings that neural-specific lengthened 3’ UTR isoforms are co-determined by ELAV/Hu factors, we address their impacts on splicing. While only a few splicing targets of Drosophila are known, ectopic expression of each of the three family members (Elav, Fne and Rbp9) alters hundreds of cassette exon and alternative last exon (ALE) splicing choices. Reciprocally, double mutants of elav/fne, but not elav alone, exhibit opposite effects on both classes of regulated mRNA processing events in larval CNS. While manipulation of Drosophila ELAV/Hu RBPs induces both exon skipping and inclusion, characteristic ELAV/Hu motifs are enriched only within introns flanking exons that are suppressed by ELAV/Hu factors. Moreover, the roles of ELAV/Hu factors in global promotion of distal ALE splicing are mechanistically linked to terminal 3’ UTR extensions in neurons, since both processes involve bypass of proximal polyadenylation signals linked to ELAV/Hu motifs downstream of cleavage sites. We corroborate the direct action of Elav in diverse modes of mRNA processing using RRM-dependent Elav-CLIP data from S2 cells. Finally, we provide evidence for conservation in mammalian neurons, which undergo broad programs of distal ALE and APA lengthening, linked to ELAV/Hu motifs downstream of regulated polyadenylation sites. Overall, ELAV/Hu RBPs orchestrate multiple broad programs of neuronal mRNA processing and isoform diversification in Drosophila and mammalian neurons.

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Section: Introductionsupporting

confidence: 61%

Section: Plos Geneticsmentioning

confidence: 60%

Section: Plos Geneticsmentioning

confidence: 98%

Section: Hierarchical Activities Of Elav/hu Factors Also Drive Globalmentioning

confidence: 98%

See 2 more Smart Citations

ELAV/Hu RNA binding proteins determine multiple programs of neural alternative splicing

Lee

Zhang

et al. 2021

PLoS Genet

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“…In summary, we found that the eMIC splicing program is recruited to neural tissues by the Elav/Fne-mediated regulation of Srrm234 3′ end processing and that, within this tissue, it modestly overlaps with splicing networks regulated by other RBPs. Interestingly, we identified several RBPs and transcriptional regulators with alternative isoforms misregulated upon eMIC insufficiency (Table S3), placing the eMIC splicing program within a dense network of neural gene expression regulation, similar to previous results from mammalian model systems 64 .…”

Section: Resultssupporting

confidence: 85%

Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

Torres-Méndez

Pop

Bonnal

et al. 2021

Preprint

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Neurons draw on alternative splicing for their increased transcriptomic complexity throughout animal phylogeny. To delve into the mechanisms controlling the assembly and evolution of this regulatory layer, we characterized the neuronal microexon program in Drosophila and compared it with that of mammals. In Drosophila, alternative splicing profiling across tissues and neuronal types showed pan-neuronal expression of this program with some variation in photoreceptors and Kenyon cells. This neuronal specificity is driven by the enhancer of microexons (eMIC) domain of Srrm234, which is expressed in neurons through post-transcriptional processing at the 3′ end of the gene by the RNA binding proteins embryonic lethal abnormal vision (Elav) and found in neurons (Fne). Both loss-of-function and misexpression of the eMIC domain lead to widespread neurological alterations associated with the skipping of short neural exons, revealing a tight regulation of this AS program in neurons. These defects emerge largely from alterations in neuronal activity, as revealed by a combination of neuronal imaging experiments and cell-type-specific rescues and in line with a strong enrichment for ion channels among genes with eMIC-dependent exons. Remarkably, we found minimal overlap of eMIC regulated exons between flies and mice, illustrating how ancient post-transcriptional programs can evolve independently in different phyla to impact distinct cellular modules while maintaining cell-type specificity.

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On the function and relevance of alternative 3′‐UTRs in gene expression regulation

Pereira-Castro

Moreira

2021

WIREs RNA

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Messanger RNA (mRNA) isoforms with alternative 3 0 -untranslated regions (3 0 -UTRs) are produced by alternative polyadenylation (APA), which occurs during transcription in most eukaryotic genes. APA fine-tunes gene expression in a cell-type-and cellular state-dependent manner. Selection of an APA site entails the binding of core cleavage and polyadenylation factors to a particular polyadenylation site localized in the pre-mRNA and is controlled by multiple regulatory determinants, including transcription, pre-mRNA cis-regulatory sequences, and protein factors. Alternative 3 0 -UTRs serve as platforms for specific RNA binding proteins and microRNAs, which regulate gene expression in a coordinated manner by controlling mRNA fate and function in the cell.Genome-wide studies illustrated the full extent of APA prevalence and revealed that specific 3 0 -UTR profiles are associated with particular cellular states and diseases. Generally, short 3 0 -UTRs are associated with proliferative and cancer cells, and long 3 0 -UTRs are mostly found in polarized and differentiated cells. Fundamental new insights on the physiological consequences of this widespread event and the molecular mechanisms involved have been revealed through single-cell studies. Publicly available comprehensive databases that cover all APA mRNA isoforms identified in many cellular states and diseases reveal specific APA signatures. Therapies tackling APA mRNA isoforms or APA regulators may be regarded as innovative and attractive tools for diagnostics or treatment of several pathologies. We highlight the function of APA and alternative 3 0 -UTRs in gene expression regulation, the control of these mechanisms, their physiological consequences, and their potential use as new biomarkers and therapeutic tools.

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ELAV and FNE Determine Neuronal Transcript Signatures through EXon-Activated Rescue

Cited by 37 publications

References 75 publications

ELAV/Hu RNA binding proteins determine multiple programs of neural alternative splicing

ELAV/Hu RNA binding proteins determine multiple programs of neural alternative splicing

Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

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