Authors: Veronica Astro, Gustavo Ramirez-Calderon, Roberta Pennucci, Jonatan Caroli, Alfonso Saera-Vila, Kelly Cardona- Londoño, Chiara Forastieri, Elisabetta Fiacco, Fatima Maksoud, Maryam Alowaysi, Elisa Sogne Andrea Falqui, Federico Gonzàlez, Nuria Montserrat, Elena Battaglioli, Andrea Mattevi, Antonio Adamo

Institutions:

  • Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Saudi Arabia
  • Department of Biology and Biotechnology, University of Pavia, Italy
  • Sequentia Biotech SL
  • Department of Medical Biotechnology and Translational Medicine, University of Milan, Italy
  • Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

Publication: iScience
Date: July 2022
Link: https://doi.org/10.1016/j.isci.2022.104665

Abstract:

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.