scholarly journals Multiple RNA regulatory pathways coordinate the activity and expression pattern of a conserved germline RNA-binding protein

2021 ◽  
Author(s):  
Mennatallah M.Y. Albarqi ◽  
Sean P. Ryder
Keyword(s):  
Cell Fate ◽  
Expression Pattern ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Control Cell ◽  
Messenger Rnas ◽  
Allelic Series ◽  
Embryo Viability ◽  
Rna Regulation ◽  
Regulatory Pathways

AbstractRNA regulation is essential to successful reproduction. Messenger RNAs delivered from parent to progeny govern early embryonic development. RNA-binding proteins (RBPs) are the key effectors of this process, controlling the translation and stability of parental transcripts to control cell fate specification events prior to zygotic gene activation. The KH-domain RBP MEX-3 is conserved from nematode to human. It was first discovered in Caenorhabditis elegans, where it is essential for anterior cell fate and embryo viability. Here, we show that mex-3 mRNA is itself regulated by several RBPs to define its unique germline spatiotemporal expression pattern. We also show that both poly(A) tail length control and translational regulation contribute to this expression pattern. Though the 3’UTR is sufficient to establish the germline expression pattern, we show that it is not essential for reproduction. An allelic series of 3’UTR deletion variants identifies repressing regions of the UTR and show that the expression pattern is not precisely coupled to reproductive health. Together, our results define the pathways that govern the spatiotemporal regulation of this highly conserved germline RBP and suggest that redundant mechanisms control MEX-3 function when RNA regulation is compromised.

scholarly journals The endogenous mex-3 3´UTR is required for germline repression and contributes to optimal fecundity in C. elegans

PLoS Genetics ◽  
2021 ◽  
Vol 17 (8) ◽  
pp. e1009775
Author(s):  
Mennatallah M. Y. Albarqi ◽  
Sean P. Ryder
Keyword(s):  
Cell Fate ◽  
Expression Pattern ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Control Cell ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Messenger Rnas ◽  
Allelic Series ◽  
Embryo Viability

RNA regulation is essential to successful reproduction. Messenger RNAs delivered from parent to progeny govern early embryonic development. RNA-binding proteins (RBPs) are the key effectors of this process, regulating the translation and stability of parental transcripts to control cell fate specification events prior to zygotic gene activation. The KH-domain RBP MEX-3 is conserved from nematode to human. It was first discovered in Caenorhabditis elegans, where it is essential for anterior cell fate and embryo viability. Here, we show that loss of the endogenous mex-3 3´UTR disrupts its germline expression pattern. An allelic series of 3´UTR deletion variants identify repressing regions of the UTR and demonstrate that repression is not precisely coupled to reproductive success. We also show that several RBPs regulate mex-3 mRNA through its 3´UTR to define its unique germline spatiotemporal expression pattern. Additionally, we find that both poly(A) tail length control and the translation initiation factor IFE-3 contribute to its expression pattern. Together, our results establish the importance of the mex-3 3´UTR to reproductive health and its expression in the germline. Our results suggest that additional mechanisms control MEX-3 function when 3´UTR regulation is compromised.

scholarly journals POS-1 and GLD-1 repress glp-1 translation through a conserved binding-site cluster

2012 ◽  
Vol 23 (23) ◽  
pp. 4473-4483 ◽  
Author(s):  
Brian M. Farley ◽  
Sean P. Ryder
Keyword(s):  
Cell Fate ◽  
Binding Sites ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Regulatory Elements ◽  
Regulatory Sequence ◽  
Regulatory Pathways ◽  
Fate Specification

RNA-binding proteins (RBPs) coordinate cell fate specification and differentiation in a variety of systems. RNA regulation is critical during oocyte development and early embryogenesis, in which RBPs control expression from maternal mRNAs encoding key cell fate determinants. The Caenorhabditis elegans Notch homologue glp-1 coordinates germline progenitor cell proliferation and anterior fate specification in embryos. A network of sequence-specific RBPs is required to pattern GLP-1 translation. Here, we map the cis-regulatory elements that guide glp-1 regulation by the CCCH-type tandem zinc finger protein POS-1 and the STAR-domain protein GLD-1. Our results demonstrate that both proteins recognize the glp-1 3′ untranslated region (UTR) through adjacent, overlapping binding sites and that POS-1 binding excludes GLD-1 binding. Both factors are required to repress glp-1 translation in the embryo, suggesting that they function in parallel regulatory pathways. It is intriguing that two equivalent POS-1–binding sites are present in the glp-1 3′ UTR, but only one, which overlaps with a translational derepression element, is functional in vivo. We propose that POS-1 regulates glp-1 mRNA translation by blocking access of other RBPs to a key regulatory sequence.

scholarly journals CAR-1 and Trailer hitch: driving mRNP granule function at the ER?

2006 ◽  
Vol 173 (2) ◽  
pp. 159-163 ◽  
Author(s):  
Carolyn J. Decker ◽  
Roy Parker
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Fate ◽  
Translational Control ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Spindle Pole ◽  
Axis Formation ◽  
Cell Fate Determination ◽  
Messenger Rnas

The targeting of messenger RNAs (mRNAs) to specific subcellular sites for local translation plays an important role in diverse cellular and developmental processes in eukaryotes, including axis formation, cell fate determination, spindle pole regulation, cell motility, and neuronal synaptic plasticity. Recently, a new conserved class of Lsm proteins, the Scd6 family, has been implicated in controlling mRNA function. Depletion or mutation of members of the Scd6 family, Caenorhabditis elegans CAR-1 and Drosophila melanogaster trailer hitch, lead to a variety of developmental phenotypes, which in some cases can be linked to alterations in the endoplasmic reticulum (ER). Scd6/Lsm proteins are RNA binding proteins and are found in RNP complexes associated with translational control of mRNAs, and these complexes can colocalize with the ER. These findings raise the possibility that localization and translational regulation of mRNAs at the ER plays a role in controlling the organization of this organelle.

scholarly journals RNA-Binding Proteins in Acute Leukemias

2020 ◽  
Vol 21 (10) ◽  
pp. 3409 ◽  
Author(s):  
Konstantin Schuschel ◽  
Matthias Helwig ◽  
Stefan Hüttelmaier ◽  
Dirk Heckl ◽  
Jan-Henning Klusmann ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Control ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genetic Diseases ◽  
Clinical Aspects ◽  
Translational Efficiency ◽  
Messenger Rnas ◽  
Acute Leukemias

Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions.

scholarly journals Compendium of Methods to Uncover RNA-Protein Interactions In Vivo

2021 ◽  
Vol 4 (1) ◽  
pp. 22
Author(s):  
Mrinmoyee Majumder ◽  
Viswanathan Palanisamy
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Expression Patterns ◽  
Control Of Gene Expression ◽  
Regulatory Pathways ◽  
Advantages And Disadvantages ◽  
Protein Nucleic Acid

Control of gene expression is critical in shaping the pro-and eukaryotic organisms’ genotype and phenotype. The gene expression regulatory pathways solely rely on protein–protein and protein–nucleic acid interactions, which determine the fate of the nucleic acids. RNA–protein interactions play a significant role in co- and post-transcriptional regulation to control gene expression. RNA-binding proteins (RBPs) are a diverse group of macromolecules that bind to RNA and play an essential role in RNA biology by regulating pre-mRNA processing, maturation, nuclear transport, stability, and translation. Hence, the studies aimed at investigating RNA–protein interactions are essential to advance our knowledge in gene expression patterns associated with health and disease. Here we discuss the long-established and current technologies that are widely used to study RNA–protein interactions in vivo. We also present the advantages and disadvantages of each method discussed in the review.

scholarly journals Nucleocytoplasmic Transport of RNA-Binding Proteins Regulates Neural Stem Cell Fates 

2020 ◽  
Author(s):  
Melissa J. MacPherson ◽  
Sarah L Erickson ◽  
Drayden Kopp ◽  
Pengqiang Wen ◽  
Mohammadreza Aghanoori ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neurodevelopmental Disorder ◽  
Neural Progenitor ◽  
Nucleocytoplasmic Transport ◽  
Transcriptional Level ◽  
Cell Fates ◽  
Cell Fate Decisions

Abstract The formation of the cerebral cortex requires balanced expansion and differentiation of neural progenitor cells, the fate choice of which requires regulation at many steps of gene expression. As progenitor cells often exhibit transcriptomic stochasticity, the ultimate output of cell fate-determining genes must be carefully controlled at the post-transcriptional level, but how this is orchestrated is poorly understood. Here we report that de novo missense variants in an RNA-binding protein CELF2 cause human cortical malformations and perturb neural progenitor cell fate decisions in mice by disrupting the nucleocytoplasmic transport of CELF2. In self-renewing neural progenitors, CELF2 is localized in the cytoplasm where it binds and coordinates mRNAs that encode cell fate regulators and neurodevelopmental disorder-related factors. The translocation of CELF2 into the nucleus releases mRNAs for translation and thereby triggers neural progenitor differentiation. Our results reveal a mechanism by which transport of CELF2 between discrete subcellular compartments orchestrates an RNA regulon to instruct cell fates in cerebral cortical development.

Post-transcriptional regulation in hematopoiesis: RNA binding proteins take control

2019 ◽  
Vol 97 (1) ◽  
pp. 10-20 ◽  
Author(s):  
Laura P.M.H. de Rooij ◽  
Derek C.H. Chan ◽  
Ava Keyvani Chahi ◽  
Kristin J. Hope
Keyword(s):  
Transcriptional Regulation ◽  
Stem Cell ◽  
Cell Fate ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Control Of Gene Expression ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Post Transcriptional Regulation

Normal hematopoiesis is sustained through a carefully orchestrated balance between hematopoietic stem cell (HSC) self-renewal and differentiation. The functional importance of this axis is underscored by the severity of disease phenotypes initiated by abnormal HSC function, including myelodysplastic syndromes and hematopoietic malignancies. Major advances in the understanding of transcriptional regulation of primitive hematopoietic cells have been achieved; however, the post-transcriptional regulatory layer that may impinge on their behavior remains underexplored by comparison. Key players at this level include RNA-binding proteins (RBPs), which execute precise and highly coordinated control of gene expression through modulation of RNA properties that include its splicing, polyadenylation, localization, degradation, or translation. With the recent identification of RBPs having essential roles in regulating proliferation and cell fate decisions in other systems, there has been an increasing appreciation of the importance of post-transcriptional control at the stem cell level. Here we discuss our current understanding of RBP-driven post-transcriptional regulation in HSCs, its implications for normal, perturbed, and malignant hematopoiesis, and the most recent technological innovations aimed at RBP–RNA network characterization at the systems level. Emerging evidence highlights RBP-driven control as an underappreciated feature of primitive hematopoiesis, the greater understanding of which has important clinical implications.

scholarly journals A Unique Regulation Region in the 3′ UTR of HLA-G with a Promising Potential

2020 ◽  
Vol 21 (3) ◽  
pp. 900 ◽  
Author(s):  
Adi Reches ◽  
Orit Berhani ◽  
Ofer Mandelboim
Keyword(s):  
Human Leukocyte Antigen ◽  
Expression Pattern ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Leukocyte Antigen ◽  
Distinct Site ◽  
Human Leukocyte Antigen G ◽  
Classical Human Leukocyte Antigen

Human leukocyte antigen G (HLA-G) is a non-classical human leukocyte antigen (HLA) class I protein that interacts with inhibitory receptors and is commonly overexpressed in various cancers, thereby establishing itself as an inhibitory checkpoint immune ligand. It is also expressed in trophoblast cells during pregnancy and protects the fetus from immune rejection. Despite its crucial role and its intriguing expression pattern, the regulation of HLA-G’s expression is only partially understood. HLA-G’s mRNA is expressed in many tissues but the protein expression is restricted only to the cells mentioned above. Therefore, we suggest that HLA-G is post-transcriptionally regulated. Here, we reveal a distinctive site present only in the 3′ Untranslated region (UTR) of HLA-G, which might explain its unique expression pattern. Consequently, we attempted to find binding factors such as RNA binding proteins (RBPs) and microRNAS (miRs) that regulate HLA-G expression by interacting with this distinct site present in its 3′ UTR. Our research indicates that this site should be further studied in order to reveal its significance.

scholarly journals The Dynamics of P Granule Liquid Droplets Are Regulated by the Caenorhabditis elegans Germline RNA Helicase GLH-1 via Its ATP Hydrolysis Cycle

Genetics ◽  
2020 ◽  
Vol 215 (2) ◽  
pp. 421-434 ◽  
Author(s):  
Wenjun Chen ◽  
Yabing Hu ◽  
Charles F. Lang ◽  
Jordan S. Brown ◽  
Sierra Schwabach ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Rna Binding ◽  
Atp Hydrolysis ◽  
Rna Binding Proteins ◽  
Rna Helicase ◽  
Liquid Droplets ◽  
P Granules ◽  
Link Type ◽  
Show Evidence

P granules are phase-separated liquid droplets that play important roles in the maintenance of germ cell fate in Caenorhabditis elegans. Both the localization and formation of P granules are highly dynamic, but mechanisms that regulate such processes remain poorly understood. Here, we show evidence that the VASA-like germline RNA helicase GLH-1 couples distinct steps of its ATPase hydrolysis cycle to control the formation and disassembly of P granules. In addition, we found that the phenylalanine-glycine-glycine repeats in GLH-1 promote its localization at the perinucleus. Proteomic analyses of the GLH-1 complex with a GLH-1 mutation that interferes with P granule disassembly revealed transient interactions of GLH-1 with several Argonautes and RNA-binding proteins. Finally, we found that defects in recruiting the P granule component PRG-1 to perinuclear foci in the adult germline correlate with the fertility defects observed in various GLH-1 mutants. Together, our results highlight the versatile roles of an RNA helicase in controlling the formation of liquid droplets in space and time.

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