scholarly journals Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2)

2021 ◽  
Author(s):  
Shilpita Karmakar ◽  
Oscar Ramirez ◽  
Kiran V. Paul ◽  
Abhishek K. Gupta ◽  
Valentina Botti ◽  
...  
Keyword(s):  
Cell Fate ◽  
Rna Binding ◽  
Asymmetric Cell Division ◽  
Elongation Factor ◽  
Cell Fate Decisions ◽  
Translational Repressor ◽  
Binding Partners ◽  
Genome Wide ◽  
Polysome Profiling ◽  
Eukaryotic Elongation Factor

ABSTRACTMusashi 2 (MSI2) is an RNA binding protein (RBP) that regulates asymmetric cell division and cell fate decisions in normal and cancer stem cells. MSI2 appears to repress translation by binding to 3’ untranslated regions (3’UTRs) of mRNA, but the identity of functional targets remains unknown. Here we used iCLIP to identify direct RNA binding partners of MSI2 and integrated these data with polysome profiling to obtain insights into MSI2 function. iCLIP revealed specific MSI2 binding to thousands of target mRNAs largely in 3’UTRs, but translational differences were restricted to a small fraction of these transcripts, indicating that MSI2 regulation is not triggered by simple binding. Instead, the functional targets identified here were bound at higher density and contain more “U/TAG” motifs compared to targets bound non-productively. To further distinguish direct and indirect targets, MSI2 was acutely depleted. Surprisingly, only 50 transcripts were found to undergo translational induction on acute MSI2 loss. Eukaryotic elongation factor 3A (EIF3A) was determined to be an immediate, direct target. We propose that MSI2 down-regulation of EIF3A amplifies these effects on the proteome. Our results also underscore the challenges in defining functional targets of RBP since mere binding does not imply a discernible functional interaction.

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.

scholarly journals Musashi-2 controls cell fate, lineage bias, and TGF-β signaling in HSCs

2014 ◽  
Vol 211 (1) ◽  
pp. 71-87 ◽  
Author(s):  
Sun-Mi Park ◽  
Raquel P. Deering ◽  
Yuheng Lu ◽  
Patrick Tivnan ◽  
Steve Lianoglou ◽  
...  
Keyword(s):  
Cell Fate ◽  
Rna Binding ◽  
Asymmetric Cell Division ◽  
Cell Function ◽  
Rna Binding Protein ◽  
Transcriptome Profiling ◽  
Hematopoietic Stem ◽  
Rna Translation ◽  
Important Regulator ◽  
Global Transcriptome

Hematopoietic stem cells (HSCs) are maintained through the regulation of symmetric and asymmetric cell division. We report that conditional ablation of the RNA-binding protein Msi2 results in a failure of HSC maintenance and engraftment caused by a loss of quiescence and increased commitment divisions. Contrary to previous studies, we found that these phenotypes were independent of Numb. Global transcriptome profiling and RNA target analysis uncovered Msi2 interactions at multiple nodes within pathways that govern RNA translation, stem cell function, and TGF-β signaling. Msi2-null HSCs are insensitive to TGF-β–mediated expansion and have decreased signaling output, resulting in a loss of myeloid-restricted HSCs and myeloid reconstitution. Thus, Msi2 is an important regulator of the HSC translatome and balances HSC homeostasis and lineage bias.

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 p53 modifications: exquisite decorations of the powerful guardian

2019 ◽  
Vol 11 (7) ◽  
pp. 564-577 ◽  
Author(s):  
Yanqing Liu ◽  
Omid Tavana ◽  
Wei Gu
Keyword(s):  
Cell Fate ◽  
Posttranslational Modifications ◽  
Stress Responses ◽  
Developmental Disorders ◽  
Adenosine Diphosphate ◽  
Independent Action ◽  
Cell Fate Decisions ◽  
Viral Binding ◽  
Binding Partners ◽  
Related Pathway

AbstractThe last 40 years have witnessed how p53 rose from a viral binding protein to a central factor in both stress responses and tumor suppression. The exquisite regulation of p53 functions is of vital importance for cell fate decisions. Among the multiple layers of mechanisms controlling p53 function, posttranslational modifications (PTMs) represent an efficient and precise way. Major p53 PTMs include phosphorylation, ubiquitination, acetylation, and methylation. Meanwhile, other PTMs like sumoylation, neddylation, O-GlcNAcylation, adenosine diphosphate (ADP)-ribosylation, hydroxylation, and β-hydroxybutyrylation are also shown to play various roles in p53 regulation. By independent action or interaction, PTMs affect p53 stability, conformation, localization, and binding partners. Deregulation of the PTM-related pathway is among the major causes of p53-associated developmental disorders or diseases, especially in cancers. This review focuses on the roles of different p53 modification types and shows how these modifications are orchestrated to produce various outcomes by modulating p53 activities or targeted to treat different diseases caused by p53 dysregulation.

scholarly journals Large-Scale Profiling of RBP-circRNA Interactions from Public CLIP-Seq Datasets

2019 ◽  
Author(s):  
Minzhe Zhang ◽  
Tao Wang ◽  
Guanghua Xiao ◽  
Yang Xie
Keyword(s):  
Large Scale ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Read Length ◽  
Circular Rnas ◽  
Binding Partners ◽  
Genome Wide ◽  
Wide Scale ◽  
And Function ◽  
Short Read Length

Circular RNAs are a special type of RNAs which recently attracted a lot of research interest in studying its formation and function. RNA binding proteins (RBPs) that bind circRNAs are important in these processes but are relatively less studied. CLIP-Seq technology has been invented and applied to profile RBP-RNA interactions on the genome-wide scale. While mRNAs are usually the focus of CLIP-Seq experiments, RBP-circRNA interactions could also be identified through specialized analysis of CLIP-Seq datasets. However, many technical difficulties are involved in this process, such as the usually short read length of CLIP-Seq reads. In this study, we created a pipeline called Clirc specialized for profiling circRNAs in CLIP-Seq data and analyzing the characteristics of RBP- circRNAs interactions. In conclusion, this is one of the first few studies to investigate circRNAs and their binding partners through repurposing CLIP-Seq datasets to our knowledge, and we hope our work will become a valuable resource for future studies into the biogenesis and function of circRNAs. Clirc software is available at https://github.com/Minzhe/Clirc

Genome-wide studies of nuclear receptors in cell fate decisions

2013 ◽  
Vol 24 (10-12) ◽  
pp. 706-715 ◽  
Author(s):  
Marco-Antonio Mendoza-Parra ◽  
Hinrich Gronemeyer
Keyword(s):  
Cell Fate ◽  
Nuclear Receptors ◽  
Cell Fate Decisions ◽  
Genome Wide

scholarly journals A Novel Double-stranded RNA-binding Protein, Disco Interacting Protein 1 (DIP1), Contributes to Cell Fate Decisions duringDrosophilaDevelopment

2003 ◽  
Vol 278 (39) ◽  
pp. 38040-38050 ◽  
Author(s):  
Dorothy DeSousa ◽  
Mahua Mukhopadhyay ◽  
Peter Pelka ◽  
Xiaoli Zhao ◽  
Bijan K. Dey ◽  
...  
Keyword(s):  
Cell Fate ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Interacting Protein ◽  
Double Stranded Rna ◽  
Cell Fate Decisions

Role of nuclear-cytoplasmic protein localization during Drosophila neuroblast development

Genome ◽  
2020 ◽  
pp. 1-11
Author(s):  
Sophie E. Keegan ◽  
Sarah C. Hughes
Keyword(s):  
Cell Fate ◽  
Neurodegenerative Disorders ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Localization ◽  
Cell Activity ◽  
Cytoplasmic Protein ◽  
Cytoplasmic Localization ◽  
Cell Fate Decisions

Nuclear-cytoplasmic localization is an efficient way to regulate transcription factors and chromatin remodelers. Altering the location of existing protein pools also facilitates a more rapid response to changes in cell activity or extracellular signals. There are several examples of proteins that are regulated by nucleo-cytoplasmic shuttling, which are required for Drosophila neuroblast development. Disruption of the localization of homologs of these proteins has also been linked to several neurodegenerative disorders in humans. Drosophila has been used extensively to model the neurodegenerative disorders caused by aberrant nucleo-cytoplasmic localization. Here, we focus on the role of alternative nucleo-cytoplasmic protein localization in regulating proliferation and cell fate decisions in the Drosophila neuroblast and in neurodegenerative disorders. We also explore the analogous role of RNA binding proteins and mRNA localization in the context of regulation of nucleo-cytoplasmic localization during neural development and a role in neurodegenerative disorders.

scholarly journals RNA-Binding Proteins Direct Myogenic Cell Fate Decisions

2021 ◽  
Author(s):  
Joshua R. Wheeler ◽  
Oscar N. Whitney ◽  
Thomas O. Vogler ◽  
Eric D. Nguyen ◽  
Bradley Pawlikowski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Fate ◽  
Tissue Regeneration ◽  
Neuromuscular Disease ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Myogenic Cell ◽  
Skeletal Muscle Regeneration ◽  
Cell Fate Decisions

ABSTRACTRNA-binding proteins (RBPs) are essential for skeletal muscle regeneration and RBP dysfunction causes muscle degeneration and neuromuscular disease. How ubiquitously expressed RBPs orchestrate complex tissue regeneration and direct cell fate decisions in skeletal muscle remains poorly understood. Single cell RNA-sequencing of regenerating skeletal muscle reveals that RBP expression, including numerous neuromuscular disease-associated RBPs, is temporally regulated in skeletal muscle stem cells and correlates to stages of myogenic differentiation. By combining machine learning with RBP engagement scoring, we discover that the neuromuscular disease associated RBP Hnrnpa2b1 is a differentiation-specifying regulator of myogenesis controlling myogenic cell fate transitions during terminal differentiation. The timing of RBP expression specifies cell fate transitions by providing a layer of post-transcriptional regulation needed to coordinate stem cell fate decisions during complex tissue regeneration.

scholarly journals Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis

Science ◽  
2021 ◽  
Vol 372 (6543) ◽  
pp. 716-721
Author(s):  
Marlies P. Rossmann ◽  
Karen Hoi ◽  
Victoria Chan ◽  
Brian J. Abraham ◽  
Song Yang ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Control ◽  
Cell Function ◽  
Coenzyme Q ◽  
Elongation Factor ◽  
Erythroid Differentiation ◽  
Mitochondrial Metabolism ◽  
Dihydroorotate Dehydrogenase ◽  
Functional Link ◽  
Cell Fate Decisions

Transcription and metabolism both influence cell function, but dedicated transcriptional control of metabolic pathways that regulate cell fate has rarely been defined. We discovered, using a chemical suppressor screen, that inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) rescues erythroid differentiation in bloodless zebrafish moonshine (mon) mutant embryos defective for transcriptional intermediary factor 1 gamma (tif1γ). This rescue depends on the functional link of DHODH to mitochondrial respiration. The transcription elongation factor TIF1γ directly controls coenzyme Q (CoQ) synthesis gene expression. Upon tif1γ loss, CoQ levels are reduced, and a high succinate/α-ketoglutarate ratio leads to increased histone methylation. A CoQ analog rescues mon’s bloodless phenotype. These results demonstrate that mitochondrial metabolism is a key output of a lineage transcription factor that drives cell fate decisions in the early blood lineage.

Sign in / Sign up

Export Citation Format

Share Document