Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Madrid, Spain.
J Cardiovasc Transl Res. 2022 Dec;15(6):1239-1255. doi: 10.1007/s12265-022-10244-x. Epub 2022 Mar 30.
Alternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants, but the global impact and regulation of AS patterns are poorly understood. Here, we studied the AS profiles in heart disease, their relationship with heart development, and the regulatory mechanisms controlling AS dynamics in the mouse heart. We found that AS profiles characterized the different groups and that AS and gene expression changes affected independent genes and biological functions. Moreover, AS changes, specifically in heart disease, were associated with potential protein-protein interaction changes. While developmental transitions were mainly driven by the upregulation of MBNL1, AS changes in disease were driven by a complex regulatory network, where PTBP1 played a central role. Indeed, PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction, potentially by perturbing AS patterns.
选择性剪接 (AS) 在转录本多样性的产生中起着重要作用。在心脏中，已经描述了一些 AS 变体的作用，但 AS 模式的全局影响和调控机制仍知之甚少。在这里，我们研究了心脏疾病中的 AS 谱、它们与心脏发育的关系，以及控制小鼠心脏 AS 动力学的调控机制。我们发现，AS 谱特征可以区分不同的组别，并且 AS 和基因表达的变化影响独立的基因和生物学功能。此外，AS 的变化，特别是在心脏疾病中，与潜在的蛋白质-蛋白质相互作用的变化有关。虽然发育性转变主要是由 MBNL1 的上调驱动的，但疾病中的 AS 变化是由一个复杂的调控网络驱动的，其中 PTBP1 起着核心作用。事实上，PTBP1 的过表达足以诱导心脏肥大和舒张功能障碍，可能是通过扰乱 AS 模式。
