Targeting the histone demethylase LSD1 prevents cardiomyopathy in a mouse model of laminopathy

摘要: LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying the origin and development of pathology unknown. Herein, using mouse pluripotent embryonic stem cells (ESCs) model both harboring p.H222P Lmna mutation, we found early defects cardiac differentiation mutated ESCs dilatation hearts at E13.5, pointing to developmental disease. Using ESCs, demonstrated that LmnaH222P/+ was impaired mesodermal stage. Expression Mesp1, cardiogenic gene involved epithelial-to-mesenchymal transition epiblast cells, as well Snai1 Twist expression, decreased compared with WT course differentiation. In turn, cardiomyocyte impaired. ChIP assay H3K4me1 differentiating revealed specific decrease this histone mark on regulatory regions Mesp1 cells. Downregulation or inhibition LSD1 specifically demethylated rescued epigenetic landscape turn contraction cardiomyocytes. Inhibition pregnant mice neonatal prevented cardiomyopathy E13.5 LmnaH222P/H222P offspring adults, respectively. Thus, appeared be therapeutic target prevent cure associated laminopathy.