by Keyword: Embryonic stem-cells
Astro, V, Ramirez-Calderon, G, Pennucci, R, Caroli, J, Saera-Vila, A, Cardona-Londono, K, Forastieri, C, Fiacco, E, Maksoud, F, Alowaysi, M, Sogne, E, Falqui, A, Gonzalez, F, Montserrat, N, Battaglioli, E, Mattevi, A, Adamo, A, (2022). Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism Iscience 25, 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.
JTD Keywords: cell biology, molecular mechanism of gene regulation, omics, Bhlh transcription factor, Corest, Differentiation, Dna, Embryonic stem-cells, Heart, Lsd1, Phosphorylation, Proteins, Stem cells research, Swirm domain
