Definition of germ layer cell lineage alternative splicing programs reveals a critical role for Quaking in specifying cardiac cell fate

Fagg, W. Samuel; Liu, Naiyou; Braunschweig, Ulrich; Rothenberg, Marc E.; Widen, Steven G.; Donohue, John P.; Fair, Jeffrey H.; Weirauch, Matthew T.; Blencowe, Benjamin J.; Garcia-Blanco, Mariano A.

doi:10.1101/2020.12.22.423880

Cited by 6 publications

(5 citation statements)

References 110 publications

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“…Furthermore, the analysis of a Qki-deficient mouse model confirms the essential role of QKI in cardiac myofibrillogenesis and function (Chen et al, 2021). Consistent with these findings, another recent work compared unique alternative splicing events in three definite cell lineages differentiated from hESCs, namely, the endoderm, cardiogenic mesoderm and neuroectoderm, and showed that QKI plays a critical role in lineage toward cardiac mesoderm and the formation of cardiomyocytes, which likely occurs via its regulation of alternative splicing of Bridging Integrator1/Amphiphysin 2 (BIN1) (Fagg et al, 2020). Of note, BIN1 was previously known for its function in regulating cardiac development (Muller et al, 2003) and myofibrillogenesis (Hong et al, 2014).…”

Section: Qki Safeguards Myofibrillogenesis In Cardiac Development and Functionsupporting

confidence: 57%

The Emerging Roles of the RNA Binding Protein QKI in Cardiovascular Development and Function

Yin

Cao

Xiao

et al. 2021

Front. Cell Dev. Biol.

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RNA binding proteins (RBPs) have a broad biological and physiological function and are critical in regulating pre-mRNA posttranscriptional processing, intracellular migration, and mRNA stability. QKI, also known as Quaking, is a member of the signal transduction and activation of RNA (STAR) family, which also belongs to the heterogeneous nuclear ribonucleoprotein K- (hnRNP K-) homology domain protein family. There are three major alternatively spliced isoforms, QKI-5, QKI-6, and QKI-7, differing in carboxy-terminal domains. They share a common RNA binding property, but each isoform can regulate pre-mRNA splicing, transportation or stability differently in a unique cell type-specific manner. Previously, QKI has been known for its important role in contributing to neurological disorders. A series of recent work has further demonstrated that QKI has important roles in much broader biological systems, such as cardiovascular development, monocyte to macrophage differentiation, bone metabolism, and cancer progression. In this mini-review, we will focus on discussing the emerging roles of QKI in regulating cardiac and vascular development and function and its potential link to cardiovascular pathophysiology.

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Section: Qki Safeguards Myofibrillogenesis In Cardiac Development and Functionsupporting

confidence: 57%

The Emerging Roles of the RNA Binding Protein QKI in Cardiovascular Development and Function

Yin

Cao

Xiao

et al. 2021

Front. Cell Dev. Biol.

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“…RNA was extracted from cells as described previously [ 75 ] using a ReliaPrep RNA extraction kit (Promega, Madison, WI, USA). RNA yields were measured on a NanoDrop (Thermo Scientific) and between 100–500 ng of RNA was used for reverse transcription using the SuperScript III system (Thermo Scientific) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Comparative Analysis of Co-Cultured Amniotic Cell-Conditioned Media with Cell-Free Amniotic Fluid Reveals Differential Effects on Epithelial–Mesenchymal Transition and Myofibroblast Activation

et al. 2022

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Myofibroblast activation is a cellular response elicited by a variety of physiological or pathological insults whereby cells initiate a coordinated response intended to eradicate the insult and then revert back to a basal state. However, an underlying theme in various disease states is persistent myofibroblast activation that fails to resolve. Based on multiple observations, we hypothesized that the secreted factors harvested from co-culturing amniotic stem cells might mimic the anti-inflammatory state that cell-free amniotic fluid (AF) elicits. We optimized an amnion epithelial and amniotic fluid cell co-culture system, and tested this hypothesis in the context of myofibroblast activation. However, we discovered that co-cultured amniotic cell conditioned media (coACCM) and AF have opposing effects on myofibroblast activation: coACCM activates the epithelial–mesenchymal transition (EMT) and stimulates gene expression patterns associated with myofibroblast activation, while AF does the opposite. Intriguingly, extracellular vesicles (EVs) purified from AF are necessary and sufficient to activate EMT and inflammatory gene expression patterns, while the EV-depleted AF potently represses these responses. In summary, these data indicate that coACCM stimulates myofibroblast activation, while AF represses it. We interpret these findings to suggest that coACCM, AF, and fractionated AF represent unique biologics that elicit different cellular responses that are correlated with a wide variety of pathological states, and therefore could have broad utility in the clinic and the lab.

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“…Finally, based on the PSI values, we used the diff tool module of vast-tools software with its default parameters to perform a Bayesian inference-based differential AS analysis. The threshold of significance was set at the minimum value for absolute value of differential PSI between MS cases and controls (MV|ΔPSI|) at 0.95 confidence level greater than 10% according to the previous studies ( Fagg et al, 2020 ; Ha et al, 2021 ; Hekman et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data

Huang

Tang

et al. 2021

Front. Genet.

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Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelinating lesions in the central nervous system. Recently, the dysregulation of alternative splicing (AS) in the brain has been found to significantly influence the progression of MS. Moreover, previous studies demonstrate that many MS-related variants in the genome act as the important regulation factors of AS events and contribute to the pathogenesis of MS. However, by far, no genome-wide research about the effect of genomic variants on AS events in MS has been reported. Here, we first implemented a strategy to obtain genomic variant genotype and AS isoform average percentage spliced-in values from RNA-seq data of 142 individuals (51 MS patients and 91 controls). Then, combing the two sets of data, we performed a cis-splicing quantitative trait loci (sQTLs) analysis to identify the cis-acting loci and the affected differential AS events in MS and further explored the characteristics of these cis-sQTLs. Finally, the weighted gene coexpression network and gene set enrichment analyses were used to investigate gene interaction pattern and functions of the affected AS events in MS. In total, we identified 5835 variants affecting 672 differential AS events. The cis-sQTLs tend to be distributed in proximity of the gene transcription initiation site, and the intronic variants of them are more capable of regulating AS events. The retained intron AS events are more susceptible to influence of genome variants, and their functions are involved in protein kinase and phosphorylation modification. In summary, these findings provide an insight into the mechanism of MS.

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Definition of germ layer cell lineage alternative splicing programs reveals a critical role for Quaking in specifying cardiac cell fate

Cited by 6 publications

References 110 publications

The Emerging Roles of the RNA Binding Protein QKI in Cardiovascular Development and Function

The Emerging Roles of the RNA Binding Protein QKI in Cardiovascular Development and Function

Comparative Analysis of Co-Cultured Amniotic Cell-Conditioned Media with Cell-Free Amniotic Fluid Reveals Differential Effects on Epithelial–Mesenchymal Transition and Myofibroblast Activation

Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data

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