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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Article number104665
JournaliScience
Volume25
Issue number7
DOIs
StatePublished - Jul 15 2022

Keywords

  • Cell biology
  • Molecular mechanism of gene regulation
  • Omics
  • Stem cells research

ASJC Scopus subject areas

  • General

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