Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
DZHK (German Center for Cardiovascular Research Partner Site Berlin), Berlin, Germany.
Nat Rev Cardiol. 2023 Aug;20(8):517-530. doi: 10.1038/s41569-022-00828-0. Epub 2023 Jan 18.
Despite advances in therapeutics for heart failure and arrhythmias, a substantial proportion of patients with cardiomyopathy do not respond to interventions, indicating a need to identify novel modifiable myocardial pathobiology. Human genetic variation associated with severe forms of cardiomyopathy and arrhythmias has highlighted the crucial role of alternative splicing in myocardial health and disease, given that it determines which mature RNA transcripts drive the mechanical, structural, signalling and metabolic properties of the heart. In this Review, we discuss how the analysis of cardiac isoform expression has been facilitated by technical advances in multiomics and long-read and single-cell sequencing technologies. The resulting insights into the regulation of alternative splicing - including the identification of cardiac splice regulators as therapeutic targets and the development of a translational pipeline to evaluate splice modulators in human engineered heart tissue, animal models and clinical trials - provide a basis for improved diagnosis and therapy. Finally, we consider how the medical and scientific communities can benefit from facilitated acquisition and interpretation of splicing data towards improved clinical decision-making and patient care.
尽管心力衰竭和心律失常的治疗方法取得了进展，但相当一部分心肌病患者对干预措施没有反应，这表明需要确定新的可改变的心肌病理生物学。与严重形式的心肌病和心律失常相关的人类遗传变异突出了可变剪接在心肌健康和疾病中的关键作用，因为它决定了哪些成熟的 RNA 转录本驱动心脏的机械、结构、信号和代谢特性。在这篇综述中，我们讨论了多组学和长读长及单细胞测序技术的进步如何促进了心脏亚型表达的分析。对可变剪接的调控的深入了解——包括鉴定心脏剪接调节剂作为治疗靶点，以及开发一种转化途径来评估人类工程心脏组织、动物模型和临床试验中的剪接调节剂——为改善诊断和治疗提供了基础。最后，我们考虑了医疗和科学界如何从促进剪接数据的获取和解释中受益，以改善临床决策和患者护理。
