Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism
Summary
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. © 2022 The Author(s).
| Authors | Astro V, Ramirez-Calderon G, Pennucci R, Caroli J, Saera-Vila A, Cardona-Londoño K, Forastieri C, Fiacco E, Maksoud F, Alowaysi M, Sogne E, Falqui A, Gonzàlez F, Montserrat N, Battaglioli E, Mattevi A, Adamo A |
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| Journal | iScience |
| Publication Date | 2022 Jul 15;25(7):104665 |
| PubMed | 35856020 |
| PubMed Central | PMC9287196 |
| DOI | 10.1016/j.isci.2022.104665 |