Department of Cardiovascular Genomics and Epigenomics, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
German Centre for Cardiovascular Research (DZHK), Mannheim, Germany.
Nat Commun. 2022 Nov 4;13(1):6663. doi: 10.1038/s41467-022-34366-7.
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 report changes in chromatin compaction and localization of cardiac genes in Lmna-/- ESCs resulting in precocious activation of a transcriptional program promoting cardiomyocyte versus endothelial cell fate. This is 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. We uncover divergent functions of lamin A/C in naïve pluripotent stem cells and cardiomyocytes, which have distinct contributions to the transcriptional alterations of patients with LMNA-associated cardiomyopathy. We conclude that disruption of lamin A/C-dependent chromatin architecture in ESCs is a primary event in LMNA loss-of-function cardiomyopathy.
细胞命运选择的严格控制对于正常发育至关重要。在这里，我们表明核纤层蛋白 A/C 在胚胎干细胞（ESCs）中发挥着关键作用，它可以保护原始多能性并确保在心脏发生过程中正确的细胞命运选择。我们报告了 Lmna-/- ESCs 中染色质紧缩和心脏基因定位的变化，导致促进心肌细胞与内皮细胞命运的转录程序过早激活。这伴随着心肌细胞分化、细胞周期退出和异常收缩的提前发生。Gata4 被核纤层蛋白 A/C 的缺失激活，Gata4 的沉默或杂合不足可挽救由核纤层蛋白 A/C 缺乏引起的异常心血管细胞命运选择。我们揭示了核纤层蛋白 A/C 在原始多能干细胞和心肌细胞中的不同功能，它们对 LMNA 相关心肌病患者的转录改变有不同的贡献。我们得出结论，ESCs 中依赖核纤层蛋白 A/C 的染色质结构的破坏是 LMNA 功能丧失型心肌病的一个主要事件。
