Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias

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.

Pathogenesis of Lethal Aspiration Pneumonia in Mecp2-null Mouse Model for Rett Syndrome

“…In our laboratory, Mecp2 -null mice exhibited reduced spontaneous movement between 3 and 8 weeks of age, and died at approximately 7–10 weeks 25 . At the late stages of disease (7–10 weeks), most Mecp2 -null mice exhibited reduced mobility and severe weakness.…”

Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome

“…Nevertheless, there is evidence for symptoms affecting peripheral tissues, and the efforts to understand the impact of MECP2 mutations in the function of other systems in the organism have recently led to more detailed descriptions of phenotypes affecting the respiratory, cardiovascular, and immune systems [4, 6, 13, 14]. Symptoms affecting the gastrointestinal tract of RTT patients are common, but how the absence of MECP2 impacts intestinal function is currently unknown.…”

Genome‐wide transcriptomic and proteomic studies of Rett syndrome mouse models identify common signaling pathways and cellular functions as potential therapeutic targets

“…Two studies used a combination of four distinct neuronal cell populations including thick tufted pyramidal neurons from the motor cortex, fast‐spiking parvalbumin‐positive interneurons from the motor cortex, noradrenergic locus coeruleus neurons, and cerebellar Purkinje cells (Ehrhart et al, ; Sugino et al, ). Other studies used astrocytes (Delepine et al, ; Yasui et al, ) and microglia and peritoneal macrophages (Cronk et al, ), while others used cardiovascular progenitor cells (Hara et al, ) and cortical callosal projection neurons (Kishi et al, ). Studies using cell sources not originating from brain regions include the use of fibroblasts (Orlic‐Milacic et al, ), skeletal muscle (Gold et al, ), and blood (Sanfeliu et al, ).…”

“…Although MECP2 is expressed in a wide range of tissues, Rett syndrome is principally caused by the deficiency of MeCP2 in the cells of the brain (Chen, Akbarian, Tudor, & Jaenisch, ) and thus apart from four studies (Gold et al, ; Hara et al, ; Orlic‐Milacic et al, ; Sanfeliu et al, ), all transcriptional murine studies were confined to the brain. A handful of studies focused on the transcriptome of the whole brain (Guo et al, ; Kriaucionis et al, ; Nuber et al, ) however these studies revealed only subtle changes in gene expression which can be attributed to the brain being a heterogeneous organ consisting of many distinct functional regions that may individually be affected by the lack of Mecp2.…”