Abstract
Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure.
Highlights
Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development
MeCP2 acts as both a repressor and an activator to control the expression of various genes via recruitment of chromatin remodeling complexes such as Sin3a, histone deacetylase (HDAC) 1/2, nuclear receptor corepressor (N-CoR) / silencing mediator for retinoid and thyroid hormone receptors (SMRT), RE1-silencing transcription factor (REST) / neuron-restrictive silencer factor (NRSF), suppressor of variegation 3–9 homolog 1 (Suv39H1), histone methyltransferase, and DNA methyltransferase I1,2
We investigated the contribution of MeCP2 to cardiac development, structure, and function using an in vitro ES cell model system and an in vivo mouse model for Rett syndrome (RTT)
Summary
Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. We found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. We detected methylation of the CpG islands in the Tbx[5] locus, and showed that MeCP2 could target these sequences Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure. MeCP2 is expressed in several mouse tissues including brain, lung, skeletal muscle, and heart, its relevance to neuronal function became evident only after the finding that mutations in the MeCP2 gene cause Rett syndrome (RTT)[4,5,6]. The significance of cardiac expression of MeCP2 is unknown, these studies suggest that MeCP2 may play a functional role in cardiovascular development and physiological function. We show that MeCP2 is involved in maintaining normal cardiac gene expression and cardiomyocyte structure in the adult mouse heart
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