scholarly journals RBM20-Related Cardiomyopathy: Current Understanding and Future Options

2021 ◽  
Vol 10 (18) ◽  
pp. 4101
Author(s):  
Jan Koelemen ◽  
Michael Gotthardt ◽  
Lars M. Steinmetz ◽  
Benjamin Meder
Keyword(s):  
Regulatory Networks ◽  
Rna Binding ◽  
Rare Variants ◽  
Cell Types ◽  
Eukaryotic Cell ◽  
Binding Motif ◽  
Granule Formation ◽  
3D Genome ◽  
Organ Systems ◽  
Induced Pluripotent

Splice regulators play an essential role in the transcriptomic diversity of all eukaryotic cell types and organ systems. Recent evidence suggests a contribution of splice-regulatory networks in many diseases, such as cardiomyopathies. Adaptive splice regulators, such as RNA-binding motif protein 20 (RBM20) determine the physiological mRNA landscape formation, and rare variants in the RBM20 gene explain up to 6% of genetic dilated cardiomyopathy (DCM) cases. With ample knowledge from RBM20-deficient mice, rats, swine and induced pluripotent stem cells (iPSCs), the downstream targets and quantitative effects on splicing are now well-defined and the prerequisites for corrective therapeutic approaches are set. This review article highlights some of the recent advances in the field, ranging from aspects of granule formation to 3D genome architectures underlying RBM20-related cardiomyopathy. Promising therapeutic strategies are presented and put into context with the pathophysiological characteristics of RBM20-related diseases.

scholarly journals Towards an autologous iPSC-derived patient-on-a-chip

2018 ◽  
Author(s):  
Anja Patricia Ramme ◽  
Leopold Koenig ◽  
Tobias Hasenberg ◽  
Christine Schwenk ◽  
Corinna Magauer ◽  
...  
Keyword(s):  
Drug Testing ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Organ Differentiation ◽  
Stem Cell Source ◽  
Organ Systems ◽  
On Chip ◽  
Induced Pluripotent ◽  
Organ Models ◽  
Model Platform

AbstractMicrophysiological systems are fundamental for progressing towards a global paradigm shift in drug development through the generation of patient-on-a-chip models. An increasing number of single- and multi-organ systems have been adopted by the pharmaceutical and cosmetic industries for predictive substance testing. These models run on heterogeneous tissues and cell types from different donors. However, a patient is an individual. Therefore, patient-on-a-chip systems need to be built from tissues from one autologous source. Individual on-chip organ differentiation from a single induced pluripotent stem cell source could provide a solution to this challenge.We designed a four-organ chip based on human physiology. It enables the interconnection of miniaturized human intestine, liver, brain and kidney equivalents. All four organ models were predifferentiated from induced pluripotent stem cells from the same healthy donor and integrated into the microphysiological system. The cross talk led to further differentiation over a 14-day cultivation period under pulsatile blood flow conditions in one common medium deprived of growth factors. This model platform will pave the way for disease induction and subsequent drug testing.

Lessons and Challenges

2014 ◽  
Author(s):  
Günter P. Wagner
Keyword(s):  
Empirical Data ◽  
Population Biology ◽  
Regulatory Networks ◽  
Cell Types ◽  
Theory Of Evolution ◽  
Developmental Evolution ◽  
Hard Time ◽  
Organ Systems ◽  
Gene Regulatory ◽  
Biological Entities

This book has argued for the reality of a class of biological entities that have a hard time finding their place in a theory of evolution based on genetics and population biology. These entities, or developmental types, include cell types, homologs, and body plans. The book has also provided examples that already have empirical data to see whether such ideas are contradicted by known facts about certain well-studied organ systems, like limbs, skin appendages, and flowers. This concluding chapter summarizes the book's central claims about homology, characters and character identity, and cooperativity in gene regulatory networks. It also discusses some of the lessons derived from reviewing the literature on these paradigms of devo-evo research as well as the challenges inherent in this perspective of developmental evolution.

scholarly journals Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

2021 ◽  
Vol 11 (2) ◽  
pp. 130
Author(s):  
Paloma Jordà ◽  
Rocío Toro ◽  
Carles Diez ◽  
Joel Salazar-Mendiguchía ◽  
Anna Fernandez-Falgueras ◽  
...  
Keyword(s):  
Rna Binding ◽  
Preventive Measures ◽  
Rare Variants ◽  
Early Recognition ◽  
Splicing Factor ◽  
Binding Motif ◽  
Familial Dilated Cardiomyopathy ◽  
Specific Alternative ◽  
Personalized Approach ◽  
Malignant Arrhythmias

The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in RBM20 that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine.

scholarly journals Dynamics of alternative splicing during somatic cell reprogramming reveals functions for RNA-binding proteins CPSF3, hnRNP UL1 and TIA1

2020 ◽  
Author(s):  
Claudia Vivori ◽  
Panagiotis Papasaikas ◽  
Ralph Stadhouders ◽  
Bruno Di Stefano ◽  
Clara Berenguer Balaguer ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Types ◽  
Cell Reprogramming ◽  
Splicing Regulation ◽  
Somatic Cell Reprogramming ◽  
Transcriptional Changes ◽  
Induced Pluripotent

AbstractIn contrast to the extensively studied rewiring of epigenetic and transcriptional programs required for cell reprogramming, the dynamics of post-transcriptional changes and their associated regulatory mechanisms remain poorly understood. Here we have studied the dynamics of alternative splicing (AS) changes occurring during efficient reprogramming of mouse B cells into induced pluripotent stem (iPS) cells. These changes, generally uncoupled from transcriptional regulation, significantly overlapped with splicing programs reported during reprogramming of mouse embryonic fibroblasts (MEFs). Correlation between gene expression of potential regulators and specific clusters of AS changes enabled the identification and subsequent validation of CPSF3 and hnRNP UL1 as facilitators, and TIA1 as repressor of MEFs reprogramming. These RNA-binding proteins control partially overlapping programs of splicing regulation affecting genes involved in developmental and morphogenetic processes. Our results reveal common programs of splicing regulation during reprogramming of different cell types and identify three novel regulators of this process.

scholarly journals YAP and TAZ Mediators at the Crossroad between Metabolic and Cellular Reprogramming

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 154
Author(s):  
Giorgia Di Benedetto ◽  
Silvia Parisi ◽  
Tommaso Russo ◽  
Fabiana Passaro
Keyword(s):  
Regulatory Networks ◽  
Aerobic Glycolysis ◽  
Hippo Pathway ◽  
Induced Pluripotent Stem Cell ◽  
Direct Conversion ◽  
Cellular Reprogramming ◽  
Binding Motif ◽  
Metabolic Switch ◽  
Induced Pluripotent ◽  
The Hippo Pathway

Cell reprogramming can either refer to a direct conversion of a specialized cell into another or to a reversal of a somatic cell into an induced pluripotent stem cell. It implies a peculiar modification of the epigenetic asset and gene regulatory networks needed for a new cell, to better fit the new phenotype of the incoming cell type. Cellular reprogramming also implies a metabolic rearrangement, similar to that observed upon tumorigenesis, with a transition from oxidative phosphorylation to aerobic glycolysis. The induction of a reprogramming process requires a nexus of signaling pathways, mixing a range of local and systemic information, and accumulating evidence points to the crucial role exerted by the Hippo pathway components Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ). In this review, we will first provide a synopsis of the Hippo pathway and its function during reprogramming and tissue regeneration, then we introduce the latest knowledge on the interplay between YAP/TAZ and metabolism and, finally, we discuss the possible role of YAP/TAZ in the orchestration of the metabolic switch upon cellular reprogramming.

scholarly journals Single cell transcriptomics of the developing zebrafish lens and identification of putative controllers of lens development

2020 ◽  
Author(s):  
Dylan Farnsworth ◽  
Mason Posner ◽  
Adam Miller
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Regulatory Networks ◽  
Rna Binding ◽  
Rapid Development ◽  
Cell Types ◽  
Model System ◽  
Lens Development ◽  
Functional Studies ◽  
Open Questions

AbstractThe vertebrate lens is a valuable model system for investigating the gene expression changes that coordinate tissue differentiation due to its inclusion of two spatially separated cell types, the outer epithelial cells and the deeper denucleated fiber cells that they support. Zebrafish are a useful model system for studying lens development given the organ’s rapid development in the first several days of life in an accessible, transparent embryo. While we have strong foundational knowledge of the diverse lens crystallin proteins and the basic gene regulatory networks controlling lens development, no study has detailed gene expression in a vertebrate lens at single cell resolution. Here we report an atlas of lens gene expression in zebrafish embryos at single cell resolution through five days of development, identifying a number of novel regulators of lens development as potential targets for future functional studies. Our temporospatial expression data address open questions about the function of α-crystallins during lens development and provides the first detailed view of β- and γ-crystallin expression in and outside the lens. We describe subfunctionalization in transcription factor genes that occur as paralog pairs in the zebrafish. Finally, we examine the expression dynamics of cytoskeletal, RNA-binding, and transcription factors genes, identifying a number of novel patterns. Overall these data provide a foundation for identifying and characterizing lens developmental regulatory mechanisms and revealing targets for future functional studies with potential therapeutic impact.

scholarly journals Replication Timing Networks: a novel class of gene regulatory networks

2017 ◽  
Author(s):  
Juan Carlos Rivera-Mulia ◽  
Sebo Kim ◽  
Haitham Gabr ◽  
Abhijit Chakraborty ◽  
Ferhat Ay ◽  
...  
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Embryonic Stem ◽  
Replication Timing ◽  
Cell Types ◽  
Bipartite Networks ◽  
Transcriptional Regulatory Networks ◽  
3D Genome ◽  
Regulatory Link ◽  
Indirect Relationship

AbstractDNA replication occurs in a defined temporal order known as the replication-timing (RT) program and is regulated during development, coordinated with 3D genome organization and transcriptional activity. However, transcription and RT are not sufficiently coordinated to predict each other, suggesting an indirect relationship. Here, we exploit genome-wide RT profiles from 15 human cell types and intermediate differentiation stages derived from human embryonic stem cells to construct different types of RT regulatory networks. First, we constructed networks based on the coordinated RT changes during cell fate commitment to create highly complex RT networks composed of thousands of interactions that form specific functional sub-network communities. We also constructed directional regulatory networks based on the order of RT changes within cell lineages and identified master regulators of differentiation pathways. Finally, we explored relationships between RT networks and transcriptional regulatory networks (TRNs), by combining them into more complex circuitries of composite and bipartite networks, revealing novel trans interactions between transcription factors and downstream RT changes that were validated with ChIP-seq data. Our findings suggest a regulatory link between the establishment of cell type specific TRNs and RT control during lineage specification.

scholarly journals Principles of RNA processing from analysis of enhanced CLIP maps for 150 RNA binding proteins

2019 ◽  
Author(s):  
Eric L Van Nostrand ◽  
Gabriel A Pratt ◽  
Brian A Yee ◽  
Emily Wheeler ◽  
Steven M Blue ◽  
...  
Keyword(s):  
Rna Processing ◽  
Regulatory Networks ◽  
Large Scale ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Types ◽  
Integrated Analysis ◽  
Branch Points

AbstractA critical step in uncovering rules of RNA processing is to study the in vivo regulatory networks of RNA binding proteins (RBPs). Crosslinking and immunoprecipitation (CLIP) methods enabled mapping RBP targets transcriptome-wide, but methodological differences present challenges to large-scale integrated analysis across datasets. The development of enhanced CLIP (eCLIP) enabled the large-scale mapping of targets for 150 RBPs in K562 and HepG2, creating a unique resource of RBP interactomes profiled with a standardized methodology in the same cell types. Here we describe our analysis of 223 enhanced (eCLIP) datasets characterizing 150 RBPs in K562 and HepG2 cell lines, revealing a range of binding modalities, including highly resolved positioning around splicing signals and mRNA untranslated regions that associate with distinct RBP functions. Quantification of enrichment for repetitive and abundant multi-copy elements reveals 70% of RBPs have enrichment for non-mRNA element classes, enables identification of novel ribosomal RNA processing factors and sites and suggests that association with retrotransposable elements reflects multiple RBP mechanisms of action. Analysis of spliceosomal RBPs indicates that eCLIP resolves AQR association after intronic lariat formation (enabling identification of branch points with single-nucleotide resolution) and provides genome-wide validation for a branch point-based scanning model for 3’ splice site recognition. Further, we show that eCLIP peak co-occurrences across RBPs enables the discovery of novel co-interacting RBPs. Finally, we present a protocol for visualization of RBP:RNA complexes in the eCLIP workflow using biotin and standard chemiluminescent visualization reagents, enabling simplified confirmation of ribonucleoprotein enrichment without radioactivity. This work illustrates the value of integrated analysis across eCLIP profiling of RBPs with widely distinct functions to reveal novel RNA biology. Further, our quantification of both mRNA and other element association will enable further research to identify novel roles of RBPs in regulating RNA processing.

scholarly journals Revisiting Cell Death Responses in Fibrotic Lung Disease: Crosstalk between Structured and Non-Structured Cells

Diagnostics ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 504
Author(s):  
Kiyoharu Fukushima ◽  
Takashi Satoh ◽  
Hiroshi Kida ◽  
Atsushi Kumanogoh
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Immune Cells ◽  
Lung Fibrosis ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Cell Types ◽  
Lung Epithelial Cells ◽  
Binding Motif ◽  
Autoantibody Production

Fibrosis is a life-threatening disorder caused by excessive formation of connective tissue that can affect several critical organs. Innate immune cells are involved in the development of various disorders, including lung fibrosis. To date, several hematopoietic cell types have been implicated in fibrosis, including pro-fibrotic monocytes like fibrocytes and segregated-nucleus-containing atypical monocytes (SatMs), but the precise cellular and molecular mechanisms underlying its development remain unclear. Repetitive injury and subsequent cell death response are triggering events for lung fibrosis development. Crosstalk between lung structured and non-structured cells is known to regulate the key molecular event. We recently reported that RNA-binding motif protein 7 (RBM7) expression is highly upregulated in the fibrotic lung and plays fundamental roles in fibrosis development. RBM7 regulates nuclear degradation of NEAT1 non-coding RNA, resulting in sustained apoptosis in the lung epithelium and fibrosis. Apoptotic epithelial cells produce CXCL12, which leads to the recruitment of pro-fibrotic monocytes. Apoptosis is also the main source of autoantigens. Recent studies have revealed important functions for natural autoantibodies that react with specific sets of self-antigens and are unique to individual diseases. Here, we review recent insights into lung fibrosis development in association with crosstalk between structured cells like lung epithelial cells and non-structured cells like migrating immune cells, and discuss their relevance to acquired immunity through natural autoantibody production.

scholarly journals The H+ATPase (V-ATPase): from proton pump to signaling complex in health and disease

2020 ◽  
Author(s):  
Amity F. Eaton ◽  
Maria Merkulova ◽  
Dennis Brown
Keyword(s):  
Plasma Membrane ◽  
Proton Pump ◽  
Reproductive Tract ◽  
Cell Types ◽  
Eukaryotic Cell ◽  
Nutrient Sensing ◽  
Signaling Complex ◽  
Organ Systems ◽  
Endosomal Acidification ◽  
Intracellular Vesicles

A primary function of the H+-ATPase (or V-ATPase) is to create an electrochemical proton gradient across eukaryotic cell membranes, which energizes fundamental cellular processes. Its activity notably allows for the acidification of intracellular vesicles and organelles, which is necessary for many essential cell biological events to occur. In addition, many specialized cell types in various organ systems such as the kidney, bone, male reproductive tract, inner ear, olfactory mucosa, and more, use plasma membrane V-ATPases to perform specific activities that depend on extracellular acidification. However, it is increasingly apparent that V-ATPases are central players in many normal and pathophysiological processes that directly influence human health in many different, and sometimes unexpected ways. These include cancer, neurodegenerative diseases, diabetes, and sensory perception, as well as energy and nutrient sensing functions within cells. This review first covers the well-established role of the V-ATPase as a transmembrane proton pump in the plasma membrane and intracellular vesicles, and outlines factors contributing to its physiological regulation in different cell types. This is followed by a discussion of the more recently emerging unconventional roles for the V-ATPase, such as its role as a protein interaction hub involved in cell signaling, and the (patho)physiological implications of these interactions. Finally, the central importance of endosomal acidification and V-ATPase activity on viral infection will be discussed in the context of the current COVID-19 pandemic.

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