A therapeutic target to prevent or cure dilated cardiomyopathy associated with laminopathy.

Anne-Claire Guénantin, Imen Jebeniani, Julia Leschik, Erwan Watrin, Gisèle Bonne, Nicolas Vignier, and Michel Pucéat

Mutations in the LMNA gene in patients are responsible for dilated cardiomyopathy. The molecular mechanisms underlying the origin and development of the pathology are unknown. Using mouse pluripotent embryonic stem cells (ESCs) and a mouse model both carrying the p.H222P Lmna mutation, we found early defects in cardiac differentiation of mutated ESCs and dilation of mutated embryonic hearts at E13.5, indicating 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-mesenchymal transition of epiblast cells, as well as expression of Snai1 and Twist, were decreased in LmnaH222P/+ cells compared with WT cells during differentiation, resulting in impaired cardiomyocyte differentiation.

ChIP analysis of H3K4me1 in differentiating cells revealed a specific downregulation of this histone mark on the 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, cardiomyocyte contraction. Inhibition of LSD1 in pregnant or neonatal mice prevented cardiomyopathy in E13.5 LmnaH222P/H222P offspring and adults, respectively. Thus, LSD1 appears to be a therapeutic target to prevent or cure laminopathy-associated dilated cardiomyopathy.

 


Targeting the histone demethylase LSD1 prevents cardiomyopathy in a mouse model of laminopathy.
Anne-Claire Guénantin, Imen Jebeniani, Julia Leschik, Erwan Watrin, Gisèle Bonne, Nicolas Vignier, and Michel Pucéat
https://www.jci.org/articles/view/136488

Epigenetic reprogramming to prevent genetic cardiomyopathy.
Commentary published January 4, 2021
https://www.jci.org/articles/view/143684

Project leader: Dr Michel Pucéat, Marseille Medical Genetics (https://www.marseille-medical-genetics.org/en/m-puceat/).
 

 

25/01/2021 - 15:04