Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism

• Published in: iScience Vol. 25; no. 7; p. 104665
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 15.07.2022; Elsevier
• Subjects: Cell biology; Molecular mechanism of gene regulation; Omics; Stem cells research; Cell biology; Stem cells research; Omics; Molecular mechanism of gene regulation
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.104665

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. [Display omitted] •ubKDM1A and KDM1A+2a isoforms are fine-tuned during fetal cardiac development•Depletion of KDM1A isoforms impairs hESC differentiation into cardiac cells•KDM1A+2a ablation enhances the expression of key cardiac markers•KDM1A isoforms exhibit enzymatic-independent divergent roles during cardiogenesis Molecular mechanism of gene regulation; Cell biology; Stem cells research; Omics