Signaling through RNA-binding proteins as a cell fate regulatory mechanism

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.

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Cataloguing and Selection of mRNAs Localized to Dendrites in Neurons and Regulated by RNA-Binding Proteins in RNA Granules

Biomolecules ◽

10.3390/biom10020167 ◽

2020 ◽

Vol 10 (2) ◽

pp. 167 ◽

Cited By ~ 3

Author(s):

Ohashi ◽

Shiina

Keyword(s):

Synaptic Plasticity ◽

Cell Fate ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Memory Formation ◽

Long Term Memory ◽

Local Translation ◽

Rna Granules

Spatiotemporal translational regulation plays a key role in determining cell fate and function. Specifically, in neurons, local translation in dendrites is essential for synaptic plasticity and long-term memory formation. To achieve local translation, RNA-binding proteins in RNA granules regulate target mRNA stability, localization, and translation. To date, mRNAs localized to dendrites have been identified by comprehensive analyses. In addition, mRNAs associated with and regulated by RNA-binding proteins have been identified using various methods in many studies. However, the results obtained from these numerous studies have not been compiled together. In this review, we have catalogued mRNAs that are localized to dendrites and are associated with and regulated by the RNA-binding proteins fragile X mental retardation protein (FMRP), RNA granule protein 105 (RNG105, also known as Caprin1), Ras-GAP SH3 domain binding protein (G3BP), cytoplasmic polyadenylation element binding protein 1 (CPEB1), and staufen double-stranded RNA binding proteins 1 and 2 (Stau1 and Stau2) in RNA granules. This review provides comprehensive information on dendritic mRNAs, the neuronal functions of mRNA-encoded proteins, the association of dendritic mRNAs with RNA-binding proteins in RNA granules, and the effects of RNA-binding proteins on mRNA regulation. These findings provide insights into the mechanistic basis of protein-synthesis-dependent synaptic plasticity and memory formation and contribute to future efforts to understand the physiological implications of local regulation of dendritic mRNAs in neurons.

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Versatility of RNA-Binding Proteins in Cancer

Comparative and Functional Genomics ◽

10.1155/2012/178525 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 55

Author(s):

Laurence Wurth

Keyword(s):

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Tumor Development ◽

Posttranscriptional Control ◽

Master Regulators ◽

Binding Domains ◽

Mrna Targets ◽

Posttranscriptional Gene Regulation ◽

A Cell

Posttranscriptional gene regulation is a rapid and efficient process to adjust the proteome of a cell to a changing environment. RNA-binding proteins (RBPs) are the master regulators of mRNA processing and translation and are often aberrantly expressed in cancer. In addition to well-studied transcription factors, RBPs are emerging as fundamental players in tumor development. RBPs and their mRNA targets form a complex network that plays a crucial role in tumorigenesis. This paper describes mechanisms by which RBPs influence the expression of well-known oncogenes, focusing on precise examples that illustrate the versatility of RBPs in posttranscriptional control of cancer development. RBPs appeared very early in evolution, and new RNA-binding domains and combinations of them were generated in more complex organisms. The identification of RBPs, their mRNA targets, and their mechanism of action have provided novel potential targets for cancer therapy.

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RNA-Binding Proteins Direct Myogenic Cell Fate Decisions

10.1101/2021.03.14.435333 ◽

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.

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The Molecular Basis of Drug Discovery Targeting the Regulatory Mechanism of MAPK Signaling via the Spatial Regulation of RNA-binding Proteins

YAKUGAKU ZASSHI ◽

10.1248/yakushi.18-00189 ◽

2019 ◽

Vol 139 (1) ◽

pp. 7-12

Author(s):

Ryosuke Satoh

Keyword(s):

Drug Discovery ◽

Molecular Basis ◽

Binding Proteins ◽

Rna Binding ◽

Regulatory Mechanism ◽

Rna Binding Proteins ◽

Mapk Signaling ◽

Spatial Regulation

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RNA-Binding Proteins in Acute Leukemias

International Journal of Molecular Sciences ◽

10.3390/ijms21103409 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3409 ◽

Cited By ~ 3

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.

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Long Noncoding RNAs and RNA-Binding Proteins in Oxidative Stress, Cellular Senescence, and Age-Related Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/2062384 ◽

2017 ◽

Vol 2017 ◽

pp. 1-21 ◽

Cited By ~ 30

Author(s):

Chongtae Kim ◽

Donghee Kang ◽

Eun Kyung Lee ◽

Jae-Seon Lee

Keyword(s):

Oxidative Stress ◽

Cell Fate ◽

Cellular Senescence ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Age Related ◽

Complex Biological Process

Cellular senescence is a complex biological process that leads to irreversible cell-cycle arrest. Various extrinsic and intrinsic insults are associated with the onset of cellular senescence and frequently accompany genomic or epigenomic alterations. Cellular senescence is believed to contribute to tumor suppression, immune response, and tissue repair as well as aging and age-related diseases. Long noncoding RNAs (lncRNAs) are >200 nucleotides long, poorly conserved, and transcribed in a manner similar to that of mRNAs. They are tightly regulated during various cellular and physiological processes. Although many lncRNAs and their functional roles are still undescribed, the importance of lncRNAs in a variety of biological processes is widely recognized. RNA-binding proteins (RBPs) have a pivotal role in posttranscriptional regulation as well as in mRNA transport, storage, turnover, and translation. RBPs interact with mRNAs, other RBPs, and noncoding RNAs (ncRNAs) including lncRNAs, and they are involved in the regulation of a broad spectrum of cellular processes. Like other cell fate regulators, lncRNAs and RBPs, separately or cooperatively, are implicated in initiation and maintenance of cellular senescence, aging, and age-related diseases. Here, we review the current understanding of both lncRNAs and RBPs and their association with oxidative stress, senescence, and age-related diseases.

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Auto-regulatory feedback by RNA-binding proteins

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjz043 ◽

2019 ◽

Vol 11 (10) ◽

pp. 930-939 ◽

Cited By ~ 10

Author(s):

Michaela Müller-McNicoll ◽

Oliver Rossbach ◽

Jingyi Hui ◽

Jan Medenbach

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Transcriptional Control ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Feedback Regulation ◽

Control Of Gene Expression ◽

Cell Fate Decisions

Abstract RNA-binding proteins (RBPs) are key regulators in post-transcriptional control of gene expression. Mutations that alter their activity or abundance have been implicated in numerous diseases such as neurodegenerative disorders and various types of cancer. This highlights the importance of RBP proteostasis and the necessity to tightly control the expression levels and activities of RBPs. In many cases, RBPs engage in an auto-regulatory feedback by directly binding to and influencing the fate of their own mRNAs, exerting control over their own expression. For this feedback control, RBPs employ a variety of mechanisms operating at all levels of post-transcriptional regulation of gene expression. Here we review RBP-mediated autogenous feedback regulation that either serves to maintain protein abundance within a physiological range (by negative feedback) or generates binary, genetic on/off switches important for e.g. cell fate decisions (by positive feedback).

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