Targeting the histone demethylase LSD1 prevents cardiomyopathy in a mouse model of laminopathy
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ABSTRACT: LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying both the origin and development of the pathology are still unknown. Herein, using mouse pluripotent stem cells (ESC) as well as a mouse model, both harbouring p.H222P Lmna mutation, we found early defects in cardiac differentiation of mutated ESCs and dilatation of mutated embryonic hearts at E13.5 pointing to a developmental origin of the disease. Using mouse ESC, we demonstrate that cardiac differentiation of LmnaH222P/+ was impaired at the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene involved in epithelial-mesenchymal transition (EMT) of epiblast cells as well as Snai1 and Twist, was decreased in LmnaH222P/+ cells when compared to wild type in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. Chromatin immunoprecipitation assay of H3K4me1 in differentiating cells revealed a specific decrease of this histone mark on regulatory regions of Mesp1 and Twist in LmnaH222P/+ cells. Downregulation or inhibition of LSD1 that specifically demethylates H3K4me1 rescued the epigenetic landscape of mesodermal LmnaH222P/+ cells and in turn contraction of cardiomyocytes. Inhibition of LSD1 in pregnant mice or neonatal mice prevented cardiomyopathy in E13.5 LmnaH222P/H222P offsprings and adults, respectively. Thus LSD1 turns out to be a therapeutic target to prevent or cure dilated cardiomyopathy associated laminopathy.
ORGANISM(S): Mus musculus
PROVIDER: GSE156975 | GEO | 2020/12/21
REPOSITORIES: GEO
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