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

J Clin Invest. 2021 Jan 4;131(1):e136488. doi: 10.1172/JCI136488.


LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying the origin and development of the pathology are unknown. Herein, using mouse pluripotent embryonic stem cells (ESCs) and a mouse model both harboring the 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 ESCs, we demonstrated that cardiac differentiation of LmnaH222P/+ was impaired at the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene involved in epithelial-to-mesenchymal transition of epiblast cells, as well as Snai1 and Twist expression, was decreased in LmnaH222P/+ cells compared with WT cells in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. ChIP 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 demethylated 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 offspring and adults, respectively. Thus, LSD1 appeared to be a therapeutic target to prevent or cure dilated cardiomyopathy associated with a laminopathy.

Keywords: Cardiology; Cardiovascular disease; Development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Cardiomyopathies / enzymology*
  • Cardiomyopathies / genetics
  • Cardiomyopathies / prevention & control*
  • Cell Differentiation
  • Disease Models, Animal
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism*
  • Lamin Type A / genetics
  • Lamin Type A / metabolism
  • Laminopathies / complications*
  • Laminopathies / enzymology*
  • Laminopathies / genetics
  • Mice
  • Mice, Mutant Strains
  • Mouse Embryonic Stem Cells / enzymology
  • Mouse Embryonic Stem Cells / pathology
  • Mutation, Missense
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology


  • Lamin Type A
  • Lmna protein, mouse
  • Histone Demethylases
  • KDM1a protein, mouse