Zebrafish as a tractable model of human cardiovascular disease

Bowley, George; Kugler, Elisabeth; Wilkinson, Robert N.; Lawrie, Allan; Eeden, Freek van; Chico, Timothy J. A.; Evans, Paul C.; Noël, Emily S.; Serbanovic-Canic, Jovana

doi:10.1111/bph.15473

Cited by 79 publications

(45 citation statements)

References 162 publications

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“…Zebrafish have advanced as a widely used model system to study cardiovascular development and disease 95 . Our findings that many genes are similarly regulated by shear stress when compared to HUVEC underscore the conserved nature of shear stress responses.…”

Section: Discussionmentioning

confidence: 99%

DNA motif analysis of shear stress responsive endothelial enhancers reveals differential association of KLF and ETV/ETS binding sites with gained and lost enhancers

Siekmann

Tsaryk

Yucel

et al. 2021

Preprint

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Endothelial cells (EC) lining blood vessels are exposed to mechanical forces, such as shear stress exerted by the flowing blood. These forces control many aspects of EC biology, including vascular tone, cell migration and proliferation in addition to cell size and shape. Despite a good understanding of the genes and signaling pathways responding to shear stress, our insights into the transcriptional regulation of these responses is much more limited. In particular, we do not know the different sets of regulatory elements (enhancers) that might control increases or decreases in gene expression. Here, we set out to study changes in the chromatin landscape of human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress. To do so, we performed ChIP-Seq for H3K27 acetylation, indicative of active enhancer elements and ATAC-Seq to mark regions of open chromatin in addition to RNA-Seq on HUVEC exposed to 6 hours of laminar shear stress. Our results show a correlation of gained and lost enhancers with up- and downregulated genes, respectively. DNA motif analysis revealed an over-representation of KLF transcription factor (TF) binding sites in gained enhancers, while lost enhancers contained more ETV/ETS motifs. We validated a subset of flow responsive enhancers using luciferase-based reporter constructs and CRISPR-Cas9 mediated genome editing. Lastly, we characterized shear stress responsive genes in ECs of zebrafish embryos using RNA-Seq. Together, our results reveal the presence of shear stress responsive DNA regulatory elements and lay the groundwork for the future exploration of these elements and the TFs binding to them in controlling EC biology.

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Section: Discussionmentioning

confidence: 99%

DNA motif analysis of shear stress responsive endothelial enhancers reveals differential association of KLF and ETV/ETS binding sites with gained and lost enhancers

Siekmann

Tsaryk

Yucel

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Regulatory requirements for continual reduction, refinement and replacement of animals in research are ever present and can limit the excellence of the scientific insight obtainable. Thus, at the other end of the spectrum of animal models, Bowley et al (2021) review the utility of zebrafish to model accurately important aspects of human cardiovascular development and disease. They compare the anatomy and physiology of zebrafish and mammalian cardiovascular systems and describe zebrafish models for studying the mechanisms of a range of cardiac and vascular pathologies, pharmacological responses to cardiovascular drugs and the in vivo screening of compounds for the treatment of cardiovascular diseases.…”

Section: Linked Articlesmentioning

confidence: 99%

How good are our models of cardiovascular disease?

Sobey

Drummond

George

2022

British J Pharmacology

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“…The zebrafish offers a fully sequenced genome, which can be easily altered using standard genetic techniques at relatively low cost (in terms of time, effort, and money) (Rafferty and Quinn, 2018 ; Stoyek et al, in press ), and almost every cardiac gene has a human ortholog with analogous function (Howe et al, 2013 ). This high degree of genetic similarity has permitted researchers to recapitulate a variety of human cardiac diseases in the zebrafish (Bowley et al, in press ), which can be studied in a high throughput manner (Kithcart and MacRae, 2018 ). Functionally, the zebrafish heart has comparable heart rate, action potential morphologies, ion channels (Ravens, 2018 ), and Ca 2+ -handling proteins (van Opbergen et al, 2018b ) to human.…”

Section: Use Of Zebrafish For Optogenetic Studies Of the Heartmentioning

confidence: 99%

Seeing the Light: The Use of Zebrafish for Optogenetic Studies of the Heart

2021

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Optogenetics, involving the optical measurement and manipulation of cellular activity with genetically encoded light-sensitive proteins (“reporters” and “actuators”), is a powerful experimental technique for probing (patho-)physiological function. Originally developed as a tool for neuroscience, it has now been utilized in cardiac research for over a decade, providing novel insight into the electrophysiology of the healthy and diseased heart. Among the pioneering cardiac applications of optogenetic actuators were studies in zebrafish, which first demonstrated their use for precise spatiotemporal control of cardiac activity. Zebrafish were also adopted early as an experimental model for the use of optogenetic reporters, including genetically encoded voltage- and calcium-sensitive indicators. Beyond optogenetic studies, zebrafish are becoming an increasingly important tool for cardiac research, as they combine many of the advantages of integrative and reduced experimental models. The zebrafish has striking genetic and functional cardiac similarities to that of mammals, its genome is fully sequenced and can be modified using standard techniques, it has been used to recapitulate a variety of cardiac diseases, and it allows for high-throughput investigations. For optogenetic studies, zebrafish provide additional advantages, as the whole zebrafish heart can be visualized and interrogated in vivo in the transparent, externally developing embryo, and the relatively small adult heart allows for in situ cell-specific observation and control not possible in mammals. With the advent of increasingly sophisticated fluorescence imaging approaches and methods for spatially-resolved light stimulation in the heart, the zebrafish represents an experimental model with unrealized potential for cardiac optogenetic studies. In this review we summarize the use of zebrafish for optogenetic investigations in the heart, highlighting their specific advantages and limitations, and their potential for future cardiac research.

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Zebrafish as a tractable model of human cardiovascular disease

Cited by 79 publications

References 162 publications

DNA motif analysis of shear stress responsive endothelial enhancers reveals differential association of KLF and ETV/ETS binding sites with gained and lost enhancers

DNA motif analysis of shear stress responsive endothelial enhancers reveals differential association of KLF and ETV/ETS binding sites with gained and lost enhancers

How good are our models of cardiovascular disease?

Seeing the Light: The Use of Zebrafish for Optogenetic Studies of the Heart

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