DGK and DZHK position paper on genome editing: basic science applications and future perspective

Brandes, Ralf P.; Dueck, Anne; Engelhardt, Stefan; Kupatt, Christian; Angelis, Maria Teresa De; Leisegang, Matthias; Noble, Ferdinand le; Moretti, Alessandra; Müller, Oliver; Skryabin, Boris V.; Thum, Thomas; Wurst, Wolfgang

doi:10.1007/s00395-020-00839-3

Cited by 6 publications

(7 citation statements)

References 169 publications

(160 reference statements)

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“…In addition, mechanisms such as the binding of splicing enhancers or inhibitors known from classical alternative linear splicing are also potential factors affecting circRNA splicing. A conceivable therapeutic approach would be the modification of Alu elements using CRISPR/Cas system-based gene editing, which should lead to effects comparable to RNA editing and could thus have an influence on the genesis of circRNAs [7]. Further studies should show which circRNAs this mechanism applies to and whether this process is influenced by other factors, such as RNA-binding proteins.…”

Section: Discussionmentioning

confidence: 99%

Reduction of A-to-I RNA editing in the failing human heart regulates formation of circular RNAs

et al. 2022

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Alterations of RNA editing that affect the secondary structure of RNAs can cause human diseases. We therefore studied RNA editing in failing human hearts. Transcriptome sequencing showed that adenosine-to-inosine (A-to-I) RNA editing was responsible for 80% of the editing events in the myocardium. Failing human hearts were characterized by reduced RNA editing. This was primarily attributable to Alu elements in introns of protein-coding genes. In the failing left ventricle, 166 circRNAs were upregulated and 7 circRNAs were downregulated compared to non-failing controls. Most of the upregulated circRNAs were associated with reduced RNA editing in the host gene. ADAR2, which binds to RNA regions that are edited from A-to-I, was decreased in failing human hearts. In vitro, reduction of ADAR2 increased circRNA levels suggesting a causal effect of reduced ADAR2 levels on increased circRNAs in the failing human heart. To gain mechanistic insight, one of the identified upregulated circRNAs with a high reduction of editing in heart failure, AKAP13, was further characterized. ADAR2 reduced the formation of double-stranded structures in AKAP13 pre-mRNA, thereby reducing the stability of Alu elements and the circularization of the resulting circRNA. Overexpression of circAKAP13 impaired the sarcomere regularity of human induced pluripotent stem cell-derived cardiomyocytes. These data show that ADAR2 mediates A-to-I RNA editing in the human heart. A-to-I RNA editing represses the formation of dsRNA structures of Alu elements favoring canonical linear mRNA splicing and inhibiting the formation of circRNAs. The findings are relevant to diseases with reduced RNA editing and increased circRNA levels and provide insights into the human-specific regulation of circRNA formation.

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Section: Discussionmentioning

confidence: 99%

Reduction of A-to-I RNA editing in the failing human heart regulates formation of circular RNAs

et al. 2022

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“…Consequently, chromatin landscape modification or further recruitment of factors that lead to tailored transcriptional modulation is possible. This is extensively reviewed elsewhere (67,71,72). Hence, the limitation of strict control over endogenous gene expression in vivo that has long been a tedious work for researchers is now alleviated by the use of the RNA-guided programmable endonuclease systems associated with transcriptional modifiers (67).…”

Section: Adapting Synthetic Control Of Transcription To the Heartmentioning

confidence: 99%

“…The CRISPR toolbox is an emerging opportunity to therapeutically modulate cellular states by the use of gene or base editing and synthetic transcription. CRISPR/Cas9-based gene editing approaches for prevention of cardiovascular disease have been demonstrated (71,116). CRISPR base editors that are delivered in vivo using lipid nanoparticles were shown to efficiently and precisely modify disease-related genes in living cynomolgus monkeys (117).…”

Section: Crispr-mediated Control Of Transcription To Enhance Cardiac ...mentioning

confidence: 99%

“…Taming Cas9 expression or activity using pharmacological approaches might therefore be a prospective route for temporally restricted or pulsed endogenous gene activation, possibly reducing expected immune responses upon constitutive Cas9 expression (159) and deserves a future validation in in vivo models. Bioengineering of Cas9 proteins as well as elaborate cell-type specific and temporally resolved Cas9 expression systems (151) are therefore essential ventures for safe and limited CRISPR/Cas9 based applications (71). Protein-based anti-CRISPRs, which are accessory proteins with fewer than 200 amino acids called "anti-CRISPRs, " can function as antagonists of CRISPR systems and achieve context-specific inhibition of Cas9.…”

Section: Controlling Cas9 Function and Side-effectsmentioning

confidence: 99%

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Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

Schoger

Panàkovà

Zelarayán

2022

Front. Cardiovasc. Med.

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Molecular and genetic differences between individual cells within tissues underlie cellular heterogeneities defining organ physiology and function in homeostasis as well as in disease states. Transcriptional control of endogenous gene expression has been intensively studied for decades. Thanks to a fast-developing field of single cell genomics, we are facing an unprecedented leap in information available pertaining organ biology offering a comprehensive overview. The single-cell technologies that arose aided in resolving the precise cellular composition of many organ systems in the past years. Importantly, when applied to diseased tissues, the novel approaches have been immensely improving our understanding of the underlying pathophysiology of common human diseases. With this information, precise prediction of regulatory elements controlling gene expression upon perturbations in a given cell type or a specific context will be realistic. Simultaneously, the technological advances in CRISPR-mediated regulation of gene transcription as well as their application in the context of epigenome modulation, have opened up novel avenues for targeted therapy and personalized medicine. Here, we discuss the fast-paced advancements during the recent years and the applications thereof in the context of cardiac biology and common cardiac disease. The combination of single cell technologies and the deep knowledge of fundamental biology of the diseased heart together with the CRISPR-mediated modulation of gene regulatory networks will be instrumental in tailoring the right strategies for personalized and precision medicine in the near future. In this review, we provide a brief overview of how single cell transcriptomics has advanced our knowledge and paved the way for emerging CRISPR/Cas9-technologies in clinical applications in cardiac biomedicine.

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“…Nowadays, a bewildering number of mouse and rat models are available from a wide variety of commercial and non-commercial sources. Due to advances in transgenic techniques and especially the development of genome editing technologies [ 43 , 44 ], their number is constantly increasing. These models can substantially differ in their immunological response according to their genetic background and/or their genetic alterations and therefore may show different symptoms and vary in the severity of disease development after infection [ 45 , 46 , 47 , 48 , 49 , 50 ].…”

Section: How To Keep Them Healthymentioning

confidence: 99%

Health Monitoring of Laboratory Rodent Colonies—Talking about (R)evolution

Buchheister

Bleich

2021

Animals

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The health monitoring of laboratory rodents is essential for ensuring animal health and standardization in biomedical research. Progress in housing, gnotobiotic derivation, and hygienic monitoring programs led to enormous improvement of the microbiological quality of laboratory animals. While traditional health monitoring and pathogen detection methods still serve as powerful tools for the diagnostics of common animal diseases, molecular methods develop rapidly and not only improve test sensitivities but also allow high throughput analyses of various sample types. Concurrently, to the progress in pathogen detection and elimination, the research community becomes increasingly aware of the striking influence of microbiome compositions in laboratory animals, affecting disease phenotypes and the scientific value of research data. As repeated re-derivation cycles and strict barrier husbandry of laboratory rodents resulted in a limited diversity of the animals’ gut microbiome, future monitoring approaches will have to reform—aiming at enhancing the validity of animal experiments. This review will recapitulate common health monitoring concepts and, moreover, outline strategies and measures on coping with microbiome variation in order to increase reproducibility, replicability and generalizability.

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DGK and DZHK position paper on genome editing: basic science applications and future perspective

Cited by 6 publications

References 169 publications

Reduction of A-to-I RNA editing in the failing human heart regulates formation of circular RNAs

Reduction of A-to-I RNA editing in the failing human heart regulates formation of circular RNAs

Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

Health Monitoring of Laboratory Rodent Colonies—Talking about (R)evolution

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