Multifaceted roles of MeCP2 in cellular regulation and phase separation: implications for neurodevelopmental...

Methyl CpG binding protein 2 (MeCP2) is a chromatin-associated protein that remains enigmatic despite more than 30 years of research, primarily due to the ever-growing list of its molecular functions, and, consequently, its related pathologies. Loss of function MECP2 mutations cause the neurodevelopmental disorder Rett syndrome (RTT); in addition, dysregulation of MeCP2 expression and/ or function are involved in numerous other pathologies, but the mechanisms of MeCP2 regulation are unclear. Advancing technologies and burgeoning mechanistic theories assist our understanding of the complexity of MeCP2 but may inadvertently cloud it if not rigorously tested. Here, rather than focus on RTT, we examine relatively underexplored aspects of MeCP2, such as its dosage homeostasis at the gene and protein levels, its controversial participation in phase separation, and its overlooked role in depression and oxidative stress. All these factors may be essential to understanding the full scope of MeCP2 function in healthy and diseased states, but are relatively infrequently studied and require further criticism. The aim of this review is to discuss the esoteric facets of MeCP2 at the molecular and pathological levels and to consider to what extent they may be necessary for general MeCP2 function.