Elevated expression of MeCP2 in cardiac and skeletal tissues is detrimental for normal development

Abstract

MeCP2 plays a critical role in interpreting epigenetic signatures that command chromatin conformation and regulation of gene transcription. In spite of MeCP2's ubiquitous expression, its functions have always been considered in the context of brain physiology. In this study, we demonstrate that alterations of the normal pattern of expression of MeCP2 in cardiac and skeletal tissues are detrimental for normal development. Overexpression of MeCP2 in the mouse heart leads to embryonic lethality with cardiac septum hypertrophy and dysregulated expression of MeCP2 in skeletal tissue produces severe malformations. We further show that MeCP2's expression in the heart is developmentally regulated; further suggesting that it plays a key role in regulating transcriptional programs in non-neural tissues.

Nuclear Calcium Signaling Controls Methyl-CpG-binding Protein 2 (MeCP2) Phosphorylation on Serine 421 following Synaptic Activity

“…In light of the critical role of MeCP2 in synaptogenesis and neural circuit development (6,7,9,16,17,47,48), our findings indicate that synaptic activity-driven processes that shape synaptic connectivity via MeCP2 require calcium transients to invade the cell nucleus. Nuclear calcium, which is known to control spine density as well as length and arborization of dendrite (23), may therefore also be a key signal that instructs, through the induction of genomic responses, the formation of appropriately connected networks needed for the development of normal cognitive abilities.…”

“…Although MeCP2 is expressed in many tissues (5,6), its function may be primarily in the development of synapses and the formation of circuits in the central nervous system. Mutations in the MeCP2 gene cause the majority of cases of Rett syndrome, an X-linked dominant neurodevelopmental disorder and leading cause of mental retardation and autistic behavior in girls and women (9 -11).…”

Methyl-CpG Binding Protein 2 (MeCP2) Localizes at the Centrosome and Is Required for Proper Mitotic Spindle Organization

“…Further, the presence of wild-type microglia in Mecp2-null mice improves life span, breathing patterns, and locomotor activity (36). A role of MeCP2 for heart and skeletal development has also been proposed (37), whereas genetic polymorphisms in the MECP2 locus have been associated with increased susceptibility to the autoimmune disease lupus erythematosus (38). Eventually, a link between MeCP2 and the growth control of normal and cancer cells has been suggested by few publications (see Refs.…”

The Effect of Mecp2 on Heart Failure

“…It was found that MeCP2 overexpression results in downregulation of a crucial regulator for many endothelial cell functions, SIRT1, and contributes to the impaired angiogenic functions of endothelial cells [16]. Elevated MeCP2 expression has been reported to result in cardiac and skeletal abnormalities during development [25]. It was also reported that MeCP2 is upregulated in infarcted hearts and that inhibition of the MeCP2-upstream microRNA miR-132 decreases myocardial contractility, reparative angiogenesis and interstitial fibrosis in infarcted hearts [26].…”