The assembly and evaluation of antisense oligonucleotides applied in exon skipping for titin-based mutations in dilated cardiomyopathy

Hahn, Johannes-Martin; Neupane, Balram; Pradhan, Kabita; Zhou, Qifeng; Testa, Lauren; Pelzl, Lisann; Maleck, Carole; Gawaz, Meinrad; Gramlich, Michael

doi:10.1016/j.yjmcc.2019.04.014

Cited by 7 publications

(5 citation statements)

References 23 publications

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“…This finding is intriguing, because genetic variations in titin A-band are the leading cause of DCM [62,63]. Hence, based on our finding, it is not unreasonable to speculate that dysregulated splicing of Titin antisense 1 might be able to induce deleterious exon-skipping in the A-band of titin, which may mimic the pathologies seen in TTNtv, and that modification of this region might even be a therapeutic principle [64,65]. Hence, the current study provides new understanding of the regulation of this important gene locus.…”

Section: Discussionmentioning

confidence: 76%

Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy

Haas

Sedaghat‐Hamedani

et al. 2020

JCM

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In recent years, the genetic architecture of dilated cardiomyopathy (DCM) has been more thoroughly elucidated. However, there is still insufficient knowledge on the modifiers and regulatory principles that lead to the failure of myocardial function. The current study investigates the association of epigenome-wide DNA methylation and alternative splicing, both of which are important regulatory principles in DCM. We analyzed screening and replication cohorts of cases and controls and identified distinct transcriptomic patterns in the myocardium that differ significantly, and we identified a strong association of intronic DNA methylation and flanking exons usage (p < 2 × 10−16). By combining differential exon usage (DEU) and differential methylation regions (DMR), we found a significant change of regulation in important sarcomeric and other DCM-associated pathways. Interestingly, inverse regulation of Titin antisense non-coding RNA transcript splicing and DNA methylation of a locus reciprocal to TTN substantiate these findings and indicate an additional role for non-protein-coding transcripts. In summary, this study highlights for the first time the close interrelationship between genetic imprinting by DNA methylation and the transport of this epigenetic information towards the dynamic mRNA splicing landscape. This expands our knowledge of the genome–environment interaction in DCM besides simple gene expression regulation.

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Section: Discussionmentioning

confidence: 76%

Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy

Haas

Sedaghat‐Hamedani

et al. 2020

JCM

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“…The measurement of drain conductance current (I DS ) with changing V GS was used in the calculation of the intrinsic transconductance, g m = ΔI DS /ΔV GS and OECT characteristic curves were plotted using Origin software HL-1 Cell Culture: HL-1 cells were kindly provided by M. Gramlich (RWTH Aachen, Germany) and cultured according to published protocols in Claycomb medium (51800C, Sigma-Aldrich, Germany) supplemented with 10% fetal bovine serum (FBS) (v/v) (Eurobio, Courtaboeuf, France), 100 U mL −1 penicillin and 0.01% (w/v) streptomycin (Invitrogen, Saint Aubin, France), 0.1 mm norepinephrine (Sigma-Aldrich, Germany), and 2 mm L-glutamine (EMD Millipore, Germany). [28,54] The chip surface was coated at 37 °C for 1 h with 0.02% w/v gelatine (EMD Millipore, Germany) and 0.1% w/v fibronectin (F-1141, Sigma-Aldrich, German). Cells were seeded as 50 000 cells/chip and electrophysiological recordings were performed 6 days later at confluency.…”

Section: Methodsmentioning

confidence: 99%

Vertical Organic Electrochemical Transistors and Electronics for Low Amplitude Micro‐Organ Signals

et al. 2022

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Electrical signals are fundamental to key biological events such as brain activity, heartbeat, or vital hormone secretion. Their capture and analysis provide insight into cell or organ physiology and a number of bioelectronic medical devices aim to improve signal acquisition. Organic electrochemical transistors (OECT) have proven their capacity to capture neuronal and cardiac signals with high fidelity and amplification. Vertical PEDOT:PSS-based OECTs (vOECTs) further enhance signal amplification and device density but have not been characterized in biological applications. An electronic board with individually tuneable transistor biases overcomes fabrication induced heterogeneity in device metrics and allows quantitative biological experiments. Careful exploration of vOECT electric parameters defines voltage biases compatible with reliable transistor function in biological experiments and provides useful maximal transconductance values without influencing cellular signal generation or propagation. This permits successful application in monitoring micro-organs of prime importance in diabetes, the endocrine pancreatic islets, which are known for their far smaller signal amplitudes as compared to neurons or heart cells. Moreover, vOECTs capture their single-cell action potentials and multicellular slow potentials reflecting micro-organ organizations as well as their modulation by the physiological stimulator glucose. This opens the possibility to use OECTs in new biomedical fields well beyond their classical applications.

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“…The first is the use of antisense oligonucleotides (ASOs) to promote skipping of variant-containing exons has been explored as a potential strategy to treat pathogenic variants in titin that cause DCM ( Gramlich et al, 2015 ). ASO-mediated strategies have shown promise in both mice and cultured cells ( Gramlich et al, 2015 ; Hahn et al, 2019 ). Given that ASOs have already been approved for the treatment of other diseases ( Crooke et al, 2021 ), such as Duchenne’s muscular dystrophy, ASO-based exon skipping strategies represent an accessible strategy to treat DCM caused by certain disruptive variants in titin.…”

Section: Future Perspectives: Targeting Titin In Heart Diseasementioning

confidence: 99%

Titin: roles in cardiac function and diseases

Stroik,

Gregorich,

Raza

et al. 2024

Front. Physiol.

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The giant protein titin is an essential component of muscle sarcomeres. A single titin molecule spans half a sarcomere and mediates diverse functions along its length by virtue of its unique domains. The A-band of titin functions as a molecular blueprint that defines the length of the thick filaments, the I-band constitutes a molecular spring that determines cell-based passive stiffness, and various domains, including the Z-disk, I-band, and M-line, serve as scaffolds for stretch-sensing signaling pathways that mediate mechanotransduction. This review aims to discuss recent insights into titin’s functional roles and their relationship to cardiac function. The role of titin in heart diseases, such as dilated cardiomyopathy and heart failure with preserved ejection fraction, as well as its potential as a therapeutic target, is also discussed.

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The assembly and evaluation of antisense oligonucleotides applied in exon skipping for titin-based mutations in dilated cardiomyopathy

Cited by 7 publications

References 23 publications

Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy

Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy

Vertical Organic Electrochemical Transistors and Electronics for Low Amplitude Micro‐Organ Signals

Titin: roles in cardiac function and diseases

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