scholarly journals PTBP1 mRNA isoforms and regulation of their translation

2018 ◽  
Author(s):  
Luisa M Arake de Tacca ◽  
Mia C Pulos ◽  
Stephen N Floor ◽  
Jamie Cate
Keyword(s):  
Cell Cycle ◽  
Alternative Splicing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Translation Initiation Factor ◽  
Protein Isoforms ◽  
Initiation Factor ◽  
Dependent Manner ◽  
Mrna Isoforms

Polypyrimidine tract-binding proteins (PTBPs) are RNA binding proteins that regulate a number of post-transcriptional events. Human PTBP1 transits between the nucleus and cytoplasm and is thought to regulate RNA processes in both. However, information about PTBP1 mRNA isoforms and regulation of PTPB1 expression remain incomplete. Here we mapped the major PTBP1 mRNA isoforms in HEK293T cells, and identified alternative 5' and 3' untranslated regions (5' UTRs, 3' UTRs) as well as alternative splicing patterns in the protein coding region. We also assessed how the observed PTBP1 mRNA isoforms contribute to PTBP1 expression in different phases of the cell cycle. Previously, PTBP1 mRNAs were shown to crosslink to eukaryotic translation initiation factor 3 (eIF3). We find that eIF3 binds differently to each PTBP1 mRNA isoform in a cell cycle-dependent manner. We also observe a strong correlation between eIF3 binding to PTBP1 mRNAs and repression of PTBP1 levels during the S phase of the cell cycle. Our results provide evidence of translational regulation of PTBP1 protein levels during the cell cycle, which may affect downstream regulation of alternative splicing and translation mediated by PTBP1 protein isoforms.

scholarly journals CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lizhen Chen ◽  
Zhijie Liu ◽  
Bing Zhou ◽  
Chaoliang Wei ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Alternative Splicing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Axon Regeneration ◽  
Rna Binding Proteins ◽  
Mrna Isoforms ◽  
C Elegans ◽  
Mrna Targets

Axon injury triggers dramatic changes in gene expression. While transcriptional regulation of injury-induced gene expression is widely studied, less is known about the roles of RNA binding proteins (RBPs) in post-transcriptional regulation during axon regeneration. In C. elegans the CELF (CUGBP and Etr-3 Like Factor) family RBP UNC-75 is required for axon regeneration. Using crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq) we identify a set of genes involved in synaptic transmission as mRNA targets of UNC-75. In particular, we show that UNC-75 regulates alternative splicing of two mRNA isoforms of the SNARE Syntaxin/unc-64. In C. elegans mutants lacking unc-75 or its targets, regenerating axons form growth cones, yet are deficient in extension. Extending these findings to mammalian axon regeneration, we show that mouse Celf2 expression is upregulated after peripheral nerve injury and that Celf2 mutant mice are defective in axon regeneration. Further, mRNAs for several Syntaxins show CELF2 dependent regulation. Our data delineate a post-transcriptional regulatory pathway with a conserved role in regenerative axon extension.

scholarly journals The CELF Family of RNA Binding Proteins Is Implicated in Cell-Specific and Developmentally Regulated Alternative Splicing

2001 ◽  
Vol 21 (4) ◽  
pp. 1285-1296 ◽  
Author(s):  
Andrea N. Ladd ◽  
Nicolas Charlet-B. ◽  
Thomas A. Cooper
Keyword(s):  
Alternative Splicing ◽  
Heart Development ◽  
Binding Proteins ◽  
Rna Binding ◽  
Striated Muscle ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Protein Isoforms ◽  
Developmentally Regulated ◽  
Exon Inclusion

ABSTRACT Alternative splicing of cardiac troponin T (cTNT) exon 5 undergoes a developmentally regulated switch such that exon inclusion predominates in embryonic, but not adult, striated muscle. We previously described four muscle-specific splicing enhancers (MSEs) within introns flanking exon 5 in chicken cTNT that are both necessary and sufficient for exon inclusion in embryonic muscle. We also demonstrated that CUG-binding protein (CUG-BP) binds a conserved CUG motif within a human cTNT MSE and positively regulates MSE-dependent exon inclusion. Here we report that CUG-BP is one of a novel family of developmentally regulated RNA binding proteins that includes embryonically lethal abnormal vision-type RNA binding protein 3 (ETR-3). This family, which we call CELF proteins for CUG-BP- and ETR-3-like factors, specifically bound MSE-containing RNAs in vitro and activated MSE-dependent exon inclusion of cTNT minigenes in vivo. The expression of two CELF proteins is highly restricted to brain. CUG-BP, ETR-3, and CELF4 are more broadly expressed, and expression is developmentally regulated in striated muscle and brain. Changes in the level of expression and isoforms of ETR-3 in two different developmental systems correlated with regulated changes in cTNT splicing. A switch from cTNT exon skipping to inclusion tightly correlated with induction of ETR-3 protein expression during differentiation of C2C12 myoblasts. During heart development, the switch in cTNT splicing correlated with a transition in ETR-3 protein isoforms. We propose that ETR-3 is a major regulator of cTNT alternative splicing and that the CELF family plays an important regulatory role in cell-specific alternative splicing during normal development and disease.

Stage-Specific Switches in Alternative Pre-mRNA Splicing during Late Erythropoiesis Are Conserved from Mouse to Human

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 531-531
Author(s):  
Sherry Gee ◽  
Jonathan Villalobos ◽  
Miki Yamamoto ◽  
Tyson A. Clark ◽  
Jeong-Ah Kang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Splicing ◽  
Protein Isoforms ◽  
Comparative Genomic ◽  
Erythroid Progenitors ◽  
Mrna Isoforms ◽  
Stop Codons ◽  
Primary Mouse

Abstract Spatial and temporal regulation of alternative pre-mRNA splicing determines which exons are incorporated into mature mRNA, modulating mRNA coding capacity to ensure synthesis of appropriate protein isoforms throughout normal differentiation and development. During erythropoiesis, a stage-specific switch in pre-mRNA splicing activates incorporation of protein 4.1R exon 16, thereby increasing 4.1R affinity for spectrin and actin and mechanically strengthening red blood cell membranes. We are exploring the hypothesis that stage-specific changes in pre-mRNA splicing regulate expression of other critical genes during terminal erythropoiesis. Last year we described exon microarray and RT-PCR studies that revealed several novel pre-mRNA splicing switches in terminally differentiating human erythroid progenitors. These alternative splicing events involved well-annotated exons with consensus exon-intron boundaries, supporting a model in which these events represent a regulated alternative splicing program rather than a breakdown of splicing integrity in late erythropoiesis. Here we report additional evidence for this model by showing that several erythroid stage-specific switches in alternative pre-mRNA splicing are conserved between human and mouse. Primary mouse splenic erythroblasts from FVA-infected mice were cultured in vitro under differentiation conditions and used as the source of RNA for analysis of murine erythroid splicing events. From a total of seven internal cassette exons whose splicing was activated in late human erythroblasts, five exhibited an analogous splicing switch in murine erythroblasts. Comparative genomic analysis showed that these alternative exons are embedded in regions of unusually high sequence conservation among vertebrate species, suggesting that important regulatory signals are contained within the adjacent introns. Indeed, the flanking introns for several of these exons contain binding motifs for Fox2, an RNA binding protein and known splicing regulator for many tissue-specific splicing events. Further analysis of the conserved erythroid splicing events revealed the following: three splicing switches occur in transcripts encoding RNA binding proteins (MBNL2, HNRPLL, and SNRP70), suggesting significant changes in the RNA processing machinery of late erythroblasts; and three of these alternative exons encode premature stop codons that could induce nonsense mediated decay (NMD) and contribute to down-regulation of these genes during terminal erythropoiesis. Consistent with the latter hypothesis, inhibition of NMD in murine erythroblast cultures led to increased accumulation of mRNA isoforms containing the premature stop codons. Together these results suggest the existence of a highly regulated alternative splicing program that is critical for late erythroid differentiation.

scholarly journals Regulation of gene expression in trypanosomatids: living with polycistronic transcription

Open Biology ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 190072 ◽  
Author(s):  
Christine Clayton
Keyword(s):  
Rna Polymerase Ii ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Transcription Control ◽  
Individual Gene ◽  
Polycistronic Transcription

In trypanosomes, RNA polymerase II transcription is polycistronic and individual mRNAs are excised by trans -splicing and polyadenylation. The lack of individual gene transcription control is compensated by control of mRNA processing, translation and degradation. Although the basic mechanisms of mRNA decay and translation are evolutionarily conserved, there are also unique aspects, such as the existence of six cap-binding translation initiation factor homologues, a novel decapping enzyme and an mRNA stabilizing complex that is recruited by RNA-binding proteins. High-throughput analyses have identified nearly a hundred regulatory mRNA-binding proteins, making trypanosomes valuable as a model system to investigate post-transcriptional regulation.

eIF4E-binding proteins: new factors, new locations, new roles

2014 ◽  
Vol 42 (4) ◽  
pp. 1238-1245 ◽  
Author(s):  
Anastasiia Kamenska ◽  
Clare Simpson ◽  
Nancy Standart
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Rna Binding Proteins ◽  
Ribosomal Subunit ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
New Locations ◽  
Specific Mrnas

The cap-binding translation initiation factor eIF4E (eukaryotic initiation factor 4E) is central to protein synthesis in eukaryotes. As an integral component of eIF4F, a complex also containing the large bridging factor eIF4G and eIF4A RNA helicase, eIF4E enables the recruitment of the small ribosomal subunit to the 5′ end of mRNAs. The interaction between eIF4E and eIF4G via a YXXXXLϕ motif is regulated by small eIF4E-binding proteins, 4E-BPs, which use the same sequence to competitively bind eIF4E thereby inhibiting cap-dependent translation. Additional eIF4E-binding proteins have been identified in the last 10–15 years, characterized by the YXXXXLϕ motif, and by interactions (many of which remain to be detailed) with RNA-binding proteins, or other factors in complexes that recognize the specific mRNAs. In the present article, we focus on the metazoan 4E-T (4E-transporter)/Cup family of eIF4E-binding proteins, and also discuss very recent examples in yeast, fruitflies and humans, some of which predictably inhibit translation, while others may result in mRNA decay or even enhance translation; altogether considerably expanding our understanding of the roles of eIF4E-binding proteins in gene expression regulation.

scholarly journals Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

2017 ◽  
Vol 114 (24) ◽  
pp. 6310-6315 ◽  
Author(s):  
Richard W. P. Smith ◽  
Ross C. Anderson ◽  
Osmany Larralde ◽  
Joel W. S. Smith ◽  
Barbara Gorgoni ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Control Point ◽  
Ribosomal Subunit ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Dependent Manner ◽  
Translational Activation

Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA-specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood. Here, we address this deficit, focusing on a herpes simplex virus-1 protein, ICP27. We reveal a direct interaction with PABP that is sufficient to promote PABP recruitment and necessary for ICP27-mediated activation. PABP binds several translation factors but is primarily considered to activate translation initiation as part of the PABP–eIF4G–eIF4E complex that stimulates the initial cap-binding step. Importantly, we find that ICP27-PABP forms a complex with, and requires the activity of, eIF4G. Surprisingly, ICP27–PABP–eIF4G complexes act independently of the effects of PABP-eIF4G on cap binding to promote small ribosomal subunit recruitment. Moreover, we find that a cellular mRNA-specific regulator, Deleted in Azoospermia-like (Dazl), also employs the PABP–eIF4G interaction in a similar manner. We propose a mechanism whereby diverse RNA-binding proteins directly recruit PABP, in a non–poly(A) tail-dependent manner, to stimulate the small subunit recruitment step. This strategy may be particularly relevant to biological conditions associated with hypoadenylated mRNAs (e.g., germ cells/neurons) and/or limiting cytoplasmic PABP (e.g., viral infection, cell stress). This mechanism adds significant insight into our knowledge of mRNA-specific translational activation and the function of the PABP–eIF4G complex in translation initiation.

scholarly journals Position Specific Alternative Splicing and Gene Expression Profiles Along the Tonotopic Axis of Chick Cochlea

2021 ◽  
Vol 8 ◽  
Author(s):  
Heiyeun Koo ◽  
Jae Yeon Hwang ◽  
Sungbo Jung ◽  
Hyeyoung Park ◽  
Jinwoong Bok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Expression Profiles ◽  
Single Gene ◽  
Gene Expression Profiles ◽  
Binding Motif ◽  
Dependent Manner ◽  
Mrna Isoforms

Alternative splicing (AS) refers to the production of multiple mRNA isoforms from a single gene due to alternative selection of exons or splice sites during pre-mRNA splicing. It is a primary mechanism of gene regulation in higher eukaryotes and significantly expands the functional complexity of eukaryotic organisms, contributing to animal development and disease. Recent studies have shown that AS also influences functional diversity by affecting the transcriptomic and proteomic profiles in a position-dependent manner in a single organ. The peripheral hearing organ, the cochlea, is organized to detect sounds at different frequencies depending on its location along the longitudinal axis. This unique functional configuration, the tonotopy, is known to be facilitated by differential gene expression along the cochlear duct. We profiled transcriptome-wide gene expression and AS changes that occur within the different positions of chick cochlea. These analyses revealed distinct gene expression profiles and AS, including a splicing program that is unique to tonotopy. Changes in the expression of splicing factors PTBP3, ESRP1, and ESRP2 were demonstrated to contribute to position-specific AS. RNA-binding motif enrichment analysis near alternatively spliced exons provided further insight into the combinatorial regulation of AS at different positions by different RNA-binding proteins. These data, along with gene ontology (GO) analysis, represent a comprehensive analysis of the dynamic regulation of AS at different positions in chick cochlea.

scholarly journals Distribution of alternative untranslated regions within the mRNA of the CELF1 splicing factor affects its expression

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Arkadiusz Kajdasz ◽  
Daria Niewiadomska ◽  
Michal Sekrecki ◽  
Krzysztof Sobczak
Keyword(s):  
Alternative Splicing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Striated Muscle ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Protein Isoforms ◽  
Untranslated Regions ◽  
Splicing Isoforms

AbstractCUG-binding protein, ELAV-like Family Member 1 (CELF1) plays an important role during the development of different tissues, such as striated muscle and brain tissue. CELF1 is an RNA-binding protein that regulates RNA metabolism processes, e.g., alternative splicing, and antagonizes other RNA-binding proteins, such as Muscleblind-like proteins (MBNLs). Abnormal activity of both classes of proteins plays a crucial role in the pathogenesis of myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults. In this work, we show that alternative splicing of exons forming both the 5′ and 3′ untranslated regions (UTRs) of CELF1 mRNA is efficiently regulated during development and tissue differentiation and is disrupted in skeletal muscles in the context of DM1. Alternative splicing of the CELF1 5′UTR leads to translation of two potential protein isoforms that differ in the lengths of their N-terminal domains. We also show that the MBNL and CELF proteins regulate the distribution of mRNA splicing isoforms with different 5′UTRs and 3′UTRs and affect the CELF1 expression by changing its sensitivity to specific microRNAs or RNA-binding proteins. Together, our findings show the existence of different mechanisms of regulation of CELF1 expression through the distribution of various 5′ and 3′ UTR isoforms within CELF1 mRNA.

scholarly journals Neurogenesis: Regulation by Alternative Splicing and Related Posttranscriptional Processes

2016 ◽  
Vol 23 (5) ◽  
pp. 466-477 ◽  
Author(s):  
Enrique Lara-Pezzi ◽  
Manuel Desco ◽  
Alberto Gatto ◽  
María Victoria Gómez-Gaviro
Keyword(s):  
Alternative Splicing ◽  
Protein Function ◽  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Degradation ◽  
Protein Isoforms ◽  
Mammalian Brain ◽  
Nonsense Mediated Decay

The complexity of the mammalian brain requires highly specialized protein function and diversity. As neurons differentiate and the neuronal circuitry is established, several mRNAs undergo alternative splicing and other posttranscriptional changes that expand the variety of protein isoforms produced. Recent advances are beginning to shed light on the molecular mechanisms that regulate isoform switching during neurogenesis and the role played by specific RNA binding proteins in this process. Neurogenesis and neuronal wiring were recently shown to also be regulated by RNA degradation through nonsense-mediated decay. An additional layer of regulatory complexity in these biological processes is the interplay between alternative splicing and long noncoding RNAs. Dysregulation of posttranscriptional regulation results in defective neuronal differentiation and/or synaptic connections that lead to neurodevelopmental and psychiatric disorders.

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