scholarly journals The atypical RNA-binding protein Taf15 regulates dorsoanterior neural development through diverse mechanisms in Xenopus tropicalis

Development ◽  
2021 ◽  
Vol 148 (15) ◽  
Author(s):  
Caitlin S. DeJong ◽  
Darwin S. Dichmann ◽  
Cameron R. T. Exner ◽  
Yuxiao Xu ◽  
Richard M. Harland
Keyword(s):  
Gene Regulation ◽  
Neural Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Transcript Abundance ◽  
Fused In Sarcoma ◽  
Neural Tissues ◽  
Exon Usage ◽  
Associate Factor

ABSTRACT The FET family of atypical RNA-binding proteins includes Fused in sarcoma (FUS), Ewing's sarcoma (EWS) and the TATA-binding protein-associate factor 15 (TAF15). FET proteins are highly conserved, suggesting specialized requirements for each protein. Fus regulates splicing of transcripts required for mesoderm differentiation and cell adhesion in Xenopus, but the roles of Ews and Taf15 remain unknown. Here, we analyze the roles of maternally deposited and zygotically transcribed Taf15, which is essential for the correct development of dorsoanterior neural tissues. By measuring changes in exon usage and transcript abundance from Taf15-depleted embryos, we found that Taf15 may regulate dorsoanterior neural development through fgfr4 and ventx2.1. Taf15 uses distinct mechanisms to downregulate Fgfr4 expression, namely retention of a single intron within fgfr4 when maternal and zygotic Taf15 is depleted, and reduction in the total fgfr4 transcript when zygotic Taf15 alone is depleted. The two mechanisms of gene regulation (post-transcriptional versus transcriptional) suggest that Taf15-mediated gene regulation is target and co-factor dependent, contingent on the milieu of factors that are present at different stages of development.

scholarly journals The atypical RNA-binding protein TAF15 regulates dorsoanterior neural development through diverse mechanisms in Xenopus tropicalis.

2021 ◽  
Author(s):  
Caitlin S DeJong ◽  
Darwin S Dichmann ◽  
Cameron R.T. Exner ◽  
Yuxiao Xu ◽  
Richard M Harland
Keyword(s):  
Gene Regulation ◽  
Neural Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Intron Retention ◽  
Transcript Abundance ◽  
Fused In Sarcoma ◽  
Neural Tissues ◽  
Ewings Sarcoma

The FET family of atypical RNA-binding proteins includes Fused in sarcoma (Fus), Ewings sarcoma (EWS), and the TATA-binding protein-associate factor 15 (TAF15). All FET family members are highly conserved from fish to mammals, suggesting an independent and specialized requirement for each protein. Fus is necessary for the proper splicing of genes required for mesoderm differentiation and cell adhesion in Xenopus, but the role, if any, that EWS and TAF15 play in development remains unknown. Here we define the role maternally deposited and zygotically transcribed TAF15 plays in development. We find that TAF15 is essential for the proper development of dorsoanterial neural tissues, and by sequencing the RNA from single TAF15-depleted embryos and measuring changes in transcript abundance and exon usage we found TAF15 regulates dorsoanterior neural tissue development through regulating fgfr4 and ventx2.1. Intriguingly, we find that TAF15 uses two distinct mechanisms to downregulate FGFR4 expression: 1) retention of a single intron within fgfr4 and 2) reduction of total fgfr4 transcript. Intron retention was identified when both maternal and zygotic TAF15 is depleted, while depletion of zygotic TAF15 alone leads to regulation of fgfr4 total transcripts. In this study we find that TAF15 plays an integral and pleiotropic role in the development of dorsoanterior neural tissues and further identify two novel mechanisms of gene regulation by TAF15, suggesting TAF15 gene regulation is target and cofactor-dependent, subject to the milieu of factors that are present at different times of development.

scholarly journals RNA-binding proteins with prion-like domains in health and disease

2017 ◽  
Vol 474 (8) ◽  
pp. 1417-1438 ◽  
Author(s):  
Alice Ford Harrison ◽  
James Shorter
Keyword(s):  
Phase Transitions ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Low Complexity ◽  
Fused In Sarcoma ◽  
Heterogeneous Nuclear Ribonucleoproteins ◽  
Health And Disease ◽  
Lateral Sclerosis

Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid–liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribonucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.

scholarly journals An homeotic post-transcriptional network controlled by the RNA-binding protein RBMX

2018 ◽  
Author(s):  
Paola Zuccotti ◽  
Daniele Peroni ◽  
Valentina Potrich ◽  
Alessandro Quattrone ◽  
Erik Dassi
Keyword(s):  
Translational Control ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Transcript Abundance ◽  
Homeotic Genes ◽  
Protein Levels ◽  
Functional Regions ◽  
Cellular Phenotypes

AbstractPost-transcriptional regulation (PTR) of gene expression is a powerful determinant of protein levels and cellular phenotypes. The 5’ and 3’ untranslated regions of the mRNA (UTRs) mediate this role through sequence and secondary structure elements bound by RNA-binding proteins (RBPs) and noncoding RNAs. While functional regions in the 3’UTRs have been extensively studied, the 5’UTRs are still relatively uncharacterized. To fill this gap, here we used a computational approach based on phylogenetic conservation to identify hyper-conserved elements in human 5’UTRs (5’HCEs). Our assumption, supported by the recovery of functionally characterized elements, was that 5’HCEs would represent evolutionarily stable and hence important PTR sites.We identified over 5000 short, clustered 5’HCEs occurring in approximately 10% of human protein-coding genes. Among these, homeotic genes were highly enriched. Indeed, 52 of the 258 characterized homeotic genes contained at least one 5’HCE, including members of all four Hox clusters and several other families. Homeotic genes are essential transcriptional regulators. They drive body plan and neuromuscular development, and the role of PTR in their expression is mostly unknown. By integrating computational and experimental approaches we then identified the RBMX RNA-binding protein as the initiator of a post-transcriptional cascade regulating many such homeotic genes. RBMX is known to control its targets by modulating transcript abundance and alternative splicing. Adding to that, we observed translational control as a novel mode of regulation by this RBP.This work thus establishes RBMX as a versatile master controller of homeotic genes and of the developmental processes they drive.

RNA-binding protein dysfunction in neurodegeneration

2021 ◽  
Author(s):  
Bastian Popper ◽  
Tom Scheidt ◽  
Rico Schieweck
Keyword(s):  
Protein Expression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Binding Protein ◽  
Protein Homeostasis ◽  
Fused In Sarcoma ◽  
Mental Retardation Protein ◽  
Key Aspects ◽  
Protein Dysfunction

Abstract Protein homeostasis (proteostasis) is a prerequisite for cellular viability and plasticity. In particular, post-mitotic cells such as neurons rely on a tightly regulated safeguard system that allows for regulated protein expression. Previous investigations have identified RNA-binding proteins (RBPs) as crucial regulators of protein expression in nerve cells. However, during neurodegeneration, their ability to control the proteome is progressively disrupted. In this review, we examine the malfunction of key RBPs such as TAR DNA-binding protein 43 (TDP-43), Fused in Sarcoma (FUS), Staufen, Pumilio and fragile-X mental retardation protein (FMRP). Therefore, we focus on two key aspects of RBP dysfunctions in neurodegeneration: protein aggregation and dysregulation of their target RNAs. Moreover, we discuss how the chaperone system responds to changes in the RBP-controlled transcriptome. Based on recent findings, we propose a two-hit model in which both, harmful RBP deposits and target mRNA mistranslation contribute to neurodegeneration observed in RBPathologies.

scholarly journals RNA-binding Motif Protein 45 (Rbm45)/Developmentally Regulated RNA-binding Protein-1 (Drbp1): Association with Neurodegenerative Disorders

2018 ◽  
Vol 7 (2) ◽  
pp. 33-37
Author(s):  
Andrew G. Eck ◽  
Kevin J. Lopez ◽  
Jeffrey O. Henderson
Keyword(s):  
Neural Development ◽  
Neurodegenerative Disorders ◽  
Inclusion Bodies ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Future Research ◽  
Binding Motif ◽  
Developmentally Regulated

Neurodegenerative disorders are caused by the progressive loss of the structure and/or function of neurons, often through cell death, contributing significantly to morbidity and mortality. Cytoplasmic aggregation of proteins into inclusion bodies is a pathological characteristic of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer’s disorder (AD). These inclusion bodies have been shown to contain RNA-binding proteins participating in RNA-dependent and RNA–independent protein:protein interactions. RNA-binding motif protein 45 (RBM45), also known as developmentally regulated RNA-binding protein-1 (Drbp1), was first identified as a novel RNA binding protein in rat that functions in neural development. Advancing research has indicated a connection between the presence of human RBM45 protein cytosolic aggregates and degenerative neurological diseases. This review considers the structure, function, and distribution of RBM45 along with a look into potential future research on this multifunctional RNA-binding protein.

RNA-Binding Proteins and Translation in Neurodegenerative Disease

2020 ◽  
Author(s):  
Kent E. Duncan
Keyword(s):  
Neurodegenerative Diseases ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Potential Contribution ◽  
Fused In Sarcoma ◽  
Specific Mrnas ◽  
Ataxia Syndrome ◽  
Research Frontiers

Both RNA-binding proteins (RBPs) and translation are increasingly implicated in several neurodegenerative diseases, but their specific roles in promoting disease are not yet fully defined. This chapter critically evaluates the evidence that altered translation of specific mRNAs mediated by RNA-binding proteins plays an important role in driving specific neurodegenerative diseases. First, diseases are discussed where a causal role for RNA-binding proteins in disease appears solid, but whether this involves altered translation is less clear. The main foci here are TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Subsequently, diseases are presented where altered translation is believed to contribute, but involvement of RNA-binding proteins is less clear. These include Huntington’s and other repeat expansion disorders such as fragile X tremor/ataxia syndrome (FXTAS), where repeat-induced non-AUG-initiated (RAN) translation is a focus. The potential contribution of both canonical and non-canonical RBPs to altered translation in Parkinson’s disease is discussed. The chapter closes by proposing key research frontiers for the field to explore and outlining methodological advances that could help to address them.

scholarly journals Alternative polyadenylation: methods, mechanism, function, and role in cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yi Zhang ◽  
Lian Liu ◽  
Qiongzi Qiu ◽  
Qing Zhou ◽  
Jinwang Ding ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Single Gene ◽  
Alternative Polyadenylation ◽  
Length Change ◽  
Suppressor Gene ◽  
Gene Expressions ◽  
Related Factors ◽  
Mrna Maturation

AbstractOccurring in over 60% of human genes, alternative polyadenylation (APA) results in numerous transcripts with differing 3’ends, thus greatly expanding the diversity of mRNAs and of proteins derived from a single gene. As a key molecular mechanism, APA is involved in various gene regulation steps including mRNA maturation, mRNA stability, cellular RNA decay, and protein diversification. APA is frequently dysregulated in cancers leading to changes in oncogenes and tumor suppressor gene expressions. Recent studies have revealed various APA regulatory mechanisms that promote the development and progression of a number of human diseases, including cancer. Here, we provide an overview of four types of APA and their impacts on gene regulation. We focus particularly on the interaction of APA with microRNAs, RNA binding proteins and other related factors, the core pre-mRNA 3’end processing complex, and 3’UTR length change. We also describe next-generation sequencing methods and computational tools for use in poly(A) signal detection and APA repositories and databases. Finally, we summarize the current understanding of APA in cancer and provide our vision for future APA related research.

scholarly journals The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 552
Author(s):  
Jasmine Harley ◽  
Benjamin E. Clarke ◽  
Rickie Patani
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Mitochondrial Dysfunction ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Therapeutic Strategies ◽  
Lateral Sclerosis

RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.

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