文章基本信息

标题：Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism
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作者：Veronica Astro ; Gustavo Ramirez-Calderon ; Roberta Pennucci 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：7
页码：1-33
DOI：10.1016/j.isci.2022.104665
语种：English
出版社：Elsevier
摘要：SummaryThe 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.Graphical abstractDisplay OmittedHighlights•ubKDM1A and KDM1A+2a isoforms are fine-tuned during fetal cardiac development•Depletion of KDM1A isoforms impairs hESC differentiation into cardiac cells•KDM1A+2a ablation enhances the expression of key cardiac markers•KDM1A isoforms exhibit enzymatic-independent divergent roles during cardiogenesisMolecular mechanism of gene regulation; Cell biology; Stem cells research; Omics