Neural specificity of the RNA-binding protein Elav is achieved by post-transcriptional repression in non-neural tissues

Sanfilippo, Piero; Smibert, Peter; Duan, Hong; Lai, Eric C.

doi:10.1242/dev.141978

Cited by 18 publications

(37 citation statements)

References 60 publications

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“…We also identify likely roles for autoregulation of these RBPs. We recently re-annotated the extent of the elav 3′ UTR [ 44 ], and we find a multitude of conserved Elav binding sites on common and alternative portions of the elav 3′ UTR, although none for Pumilio (Fig. 5d ), in line with the known role of Elav in regulating its own 3′ UTR [ 45 ].…”

Section: Resultssupporting

confidence: 63%

Landscape and evolution of tissue-specific alternative polyadenylation across Drosophila species

2017

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Background Drosophila melanogaster has one of best-described transcriptomes of any multicellular organism. Nevertheless, the paucity of 3′-sequencing data in this species precludes comprehensive assessment of alternative polyadenylation (APA), which is subject to broad tissue-specific control.ResultsHere, we generate deep 3′-sequencing data from 23 developmental stages, tissues, and cell lines of D. melanogaster, yielding a comprehensive atlas of ~ 62,000 polyadenylated ends. These data broadly extend the annotated transcriptome, identify ~ 40,000 novel 3′ termini, and reveal that two-thirds of Drosophila genes are subject to APA. Furthermore, we dramatically expand the numbers of genes known to be subject to tissue-specific APA, such as 3′ untranslated region (UTR) lengthening in head and 3′ UTR shortening in testis, and characterize new tissue and developmental 3′ UTR patterns. Our thorough 3′ UTR annotations permit reassessment of post-transcriptional regulatory networks, via conserved miRNA and RNA binding protein sites. To evaluate the evolutionary conservation and divergence of APA patterns, we generate developmental and tissue-specific 3′-seq libraries from Drosophila yakuba and Drosophila virilis. We document broadly analogous tissue-specific APA trends in these species, but also observe significant alterations in 3′ end usage across orthologs. We exploit the population of functionally evolving poly(A) sites to gain clear evidence that evolutionary divergence in core polyadenylation signal (PAS) and downstream sequence element (DSE) motifs drive broad alterations in 3′ UTR isoform expression across the Drosophila phylogeny.ConclusionsThese data provide a critical resource for the Drosophila community and offer many insights into the complex control of alternative tissue-specific 3′ UTR formation and its consequences for post-transcriptional regulatory networks.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1358-0) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 63%

Landscape and evolution of tissue-specific alternative polyadenylation across Drosophila species

2017

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“…In the comparison between glia and neurons, mir-9b is down-regulated in neurons at both time points and its target genes are enriched for several GO terms related to neuron differentiation. Similarly, the two microRNAs mir-279 and mir-996 were previously described as post-transcriptional inhibitors of elav [23]. Accordingly, here we found mir-279 to be up-regulated in glia compared with neuroblasts as well as neurons at both time points.…”

Section: Discussionsupporting

confidence: 85%

“…For example, mir-124 and its target repo are often expressed in spatial reciprocity in the central nervous system [21] and mir-124 is an important regulator for nervous system development in the early embryo [22]. The RNA-binding protein elav, which serves as a neural marker gene, is also believed to be regulated post-transcriptionally by microRNAs from the mir-279/996 family [23]. Other microRNAs have been shown to have particular roles during embryogenesis.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional dynamics of microRNAs and their targets during Drosophila neurogenesis

et al. 2019

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During Drosophila melanogaster embryogenesis, tight regulation of gene expression in time and space is required for the orderly emergence of specific cell types. While the general importance of microRNAs in regulating eukaryotic gene expression has been well-established, their role in early neurogenesis remains to be addressed. In this survey, we investigate the transcriptional dynamics of microRNAs and their target transcripts during neurogenesis of Drosophila melanogaster. To this end, we use the recently developed DIV-MARIS protocol, a method for enriching specific cell types from the Drosophila embryo in vivo, to sequence cell type-specific transcriptomes. We generate dedicated small and total RNA-seq libraries for neuroblasts, neurons and glia cells at early (6–8 h after egg laying (AEL)) and late (18–22 h AEL) stage. This allows us to directly compare these transcriptomes and investigate the potential functional roles of individual microRNAs with spatiotemporal resolution genome-wide, which is beyond the capabilities of existing in situ hybridization methods. Overall, we identify 74 microRNAs that are significantly differentially expressed between the three cell types and the two developmental stages. In all cell types, predicted target genes of down-regulated microRNAs show a significant enrichment of Gene Ontology terms related to neurogenesis. We also investigate how microRNAs regulate the transcriptome by targeting transcription factors and find many candidate microRNAs with putative roles in neurogenesis. Our survey highlights the roles of microRNAs as regulators of differentiation and glioneurognesis in the fruit fly and provides distinct starting points for dedicated functional follow-up studies.

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“…Certain members of the ELAV/Hu family are broadly expressed (e.g. vertebrate ELAVL1/HuR), and we recognized that seemingly neural-specific Drosophila Elav is actually ubiquitously expressed at a low level but post-transcriptionally repressed outside of the nervous system [79]. Nevertheless, a defining feature of this family is that most ELAV/Hu members in Drosophila and vertebrates are strongly elevated or restricted to neurons [80].…”

Section: Biology Of Neuronal Elav/hu Factorsmentioning

confidence: 99%

Overlapping activities of ELAV/Hu RNA binding proteins specify multiple neural alternative splicing programs

Lee¹,

Zhang²,

Lu³

et al. 2020

Preprint

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ELAV/Hu factors are conserved RNA binding proteins 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, still little is 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. In ectopic contexts, all three members (Elav, Fne and Rbp9) induce similar and broad changes to cassette exon and alternative last exon (ALE) splicing. Reciprocally, double mutants of elav/fne, but not elav alone, have opposite effects on both types of mRNA processing events in the larval CNS. Accordingly, while fne mutants are normal, fne loss strongly enhances elav mutants with respect to neuronal differentiation. While manipulation of Drosophila ELAV/Hu factors induces both exon skipping and inclusion, motif analysis indicates their major direct effects are to suppress cassette exon usage. Moreover, we find direct analogies in their roles in global promotion of distal ALE splicing and terminal 3’ UTR extension, since both involve local suppression of proximal polyadenylation signals via ELAV/Hu binding sites downstream of cleavage sites. Finally, we provide evidence for analogous co-implementation of distal ALE and APA lengthening programs in mammalian neurons, linked to ELAV/Hu motifs downstream of regulated polyadenylation sites. Overall, ELAV/Hu proteins orchestrate multiple conserved programs of neuronal mRNA processing by suppressing alternative exons and polyadenylation sites.

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Neural specificity of the RNA-binding protein Elav is achieved by post-transcriptional repression in non-neural tissues

Cited by 18 publications

References 60 publications

Landscape and evolution of tissue-specific alternative polyadenylation across Drosophila species

Landscape and evolution of tissue-specific alternative polyadenylation across Drosophila species

Transcriptional dynamics of microRNAs and their targets during Drosophila neurogenesis

Overlapping activities of ELAV/Hu RNA binding proteins specify multiple neural alternative splicing programs

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