Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function [ATAC-seq_ESC_MUT]

Tight control of cell fate choices is crucial for normal development. Here we show that lamin A/C plays a key role in chromatin organization in embryonic stem cells (ESCs), which safeguards naïve pluripotency and ensures proper cell fate choices during cardiogenesis. We find major changes in chromatin compaction and localization of cardiac genes already in Lmna-/-ESCs resulting in precocious activation of a transcriptional program promoting cardiomyocyte versus endothelial cell fate, accompanied by premature cardiomyocyte differentiation, cell cycle withdrawal, and abnormal contractility. Gata4 is activated by lamin A/C loss and Gata4 silencing or haploinsufficiency rescues the aberrant cardiovascular cell fate choices induced by lamin A/C deficiency. Importantly, we observe divergent functions of lamin A/C in naïve pluripotent stem cells and cardiomyocytes, which has distinct contributions to the transcriptional alterations of patients with LMNA-associated cardiomyopathy. Thus, disruption of lamin A/C-dependent chromatin architecture in ESCs is a primary event in LMNA loss-of-function cardiomyopathy. Overall design: Conrol , Lmna H222P Homo, Lmna G609G Het and Lmna G609G Homo E14 Tg(Nkx2-5-EmGFP) mESCs were maintained on mitomycin treated mouse embryonic fibroblasts (MEF) in DMEM high glucose supplemented with 15% fetal bovine serum, 2 mM L-glutamine, 0.1 mM 2-mercaptoethanol, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 4.5 mg/ml D-glucose, 1% penicillin-streptomycin and 1000 U/ml leukemia inhibitory factor and were collected for ATAC-seq. Please note that each ESC_Lmna_*_ATAC_mer_RPKM_norm_mm10.bw file was generated from both replicates and is linked to the corresponding *Rep1 sample records.