Astro Veronica, Ramirez-Calderon Gustavo, Pennucci Roberta, Caroli Jonatan, Saera-Vila Alfonso, Cardona-Londoño Kelly, Forastieri Chiara, Fiacco Elisabetta, Maksoud Fatima, Alowaysi Maryam, Sogne Elisa, Falqui Andrea, Gonzàlez Federico, Montserrat Nuria, Battaglioli Elena, Mattevi Andrea, Adamo Antonio
Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia.
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
iScience. 2022 Jun 23;25(7):104665. doi: 10.1016/j.isci.2022.104665. eCollection 2022 Jul 15.
The histone demethylase KDM1A is a multi-faceted regulator of vital developmental processes, including mesodermal and cardiac tube formation during gastrulation. However, it is unknown whether the fine-tuning of KDM1A splicing isoforms, already shown to regulate neuronal maturation, is crucial for the specification and maintenance of cell identity during cardiogenesis. Here, we discovered a temporal modulation of ubKDM1A and KDM1A+2a during human and mice fetal cardiac development and evaluated their impact on the regulation of cardiac differentiation. We revealed a severely impaired cardiac differentiation in KDM1A hESCs that can be rescued by re-expressing ubKDM1A or catalytically impaired ubKDM1A-K661A, but not by KDM1A+2a or KDM1A+2a-K661A. Conversely, KDM1A+2a hESCs give rise to functional cardiac cells, displaying increased beating amplitude and frequency and enhanced expression of critical cardiogenic markers. Our findings prove the existence of a divergent scaffolding role of KDM1A splice variants, independent of their enzymatic activity, during hESC differentiation into cardiac cells.
组蛋白去甲基化酶KDM1A是重要发育过程的多面调节因子，包括原肠胚形成期间的中胚层和心脏管形成。然而，已证明可调节神经元成熟的KDM1A剪接异构体的微调对于心脏发生过程中细胞身份的指定和维持是否至关重要尚不清楚。在此，我们发现了人类和小鼠胎儿心脏发育过程中ubKDM1A和KDM1A+2a的时间调节，并评估了它们对心脏分化调节的影响。我们发现KDM1A人胚胎干细胞中的心脏分化严重受损，通过重新表达ubKDM1A或催化受损的ubKDM1A-K661A可以挽救，但KDM1A+2a或KDM1A+2a-K661A则不能。相反，KDM1A+2a人胚胎干细胞产生功能性心脏细胞，表现出跳动幅度和频率增加以及关键心脏发生标志物的表达增强。我们的研究结果证明，在人胚胎干细胞分化为心脏细胞的过程中，KDM1A剪接变体存在不同的支架作用，与其酶活性无关。
