Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism
Abstrak
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.
Topik & Kata Kunci
Penulis (17)
V. Astro
G. Ramírez-Calderón
Roberta Pennucci
Jonatan Caroli
A. Saera-Vila
Kelly J. Cardona-Londoño
C. Forastieri
E. Fiacco
Fatima Maksoud
Maryam Alowaysi
E. Sogne
A. Falqui
Federico Gonzãlez
N. Montserrat
E. Battaglioli
A. Mattevi
A. Adamo
Akses Cepat
- Tahun Terbit
- 2022
- Bahasa
- en
- Total Sitasi
- 11×
- Sumber Database
- Semantic Scholar
- DOI
- 10.1016/j.isci.2022.104665
- Akses
- Open Access ✓