Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function[RNA-seq_ESC]
Ontology highlight
ABSTRACT: 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.
Project description: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.
Project description: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.
Project description: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.
Project description: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.
Project description: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.
Project description: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.
Project description: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.
Project description: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.
Project description: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.
Project description:Mutations in the LMNA gene encoding nuclear lamins A/C cause a diverse array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the molecular perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis leading to cardiac dysfunction remains elusive. Using a novel cell-type specific Lmna deletion mouse model capable of translatome profiling, we found that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Prior to the onset of cardiac dysfunction, lamin A/C-depleted cardiomyocytes displayed nuclear envelope deterioration, disruption of the ER-golgi interface, and ER stress. Translatome profiling identified upregulation of Med25, a transcriptional co-factor involved in unfolded protein responses. Culturing Lmna-deleted cardiomyocytes in stiff hydrogels recapitulated these pathological features, confirming that cardiomyocyte-extrinsic factors contribute to the pathogenesis. Pharmacological activation of autophagy or modulation of ER stress significantly improved the cardiac function. These studies support a unified hypothesis wherein cardiomyopathy develops from autophagic impairment that exacerbates ER stress emanating from nuclear envelope deterioration.