Exploring the complexity of MECP2 function in Rett syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder that is mainly caused by mutations in the methyl-DNA-binding protein MECP2. MECP2 is an important epigenetic regulator that plays a pivotal role in neuronal gene regulation, where it has been reported to function as both a repressor and an activator. Despite extensive efforts in mechanistic studies over the past two decades, a clear consensus on how MECP2 dysfunction impacts molecular mechanisms and contributes to disease progression has not been reached. Here, we review recent insights from epigenomic, transcriptomic and proteomic studies that advance our understanding of MECP2 as an interacting hub for DNA, RNA and transcription factors, orchestrating diverse processes that are crucial for neuronal function. By discussing findings from different model systems, we identify crucial epigenetic details and cofactor interactions, enriching our understanding of the multifaceted roles of MECP2 in transcriptional regulation and chromatin structure. These mechanistic insights offer potential avenues for rational therapeutic design for RTT. Mutations in the gene encoding the methyl-DNA-binding protein MECP2 cause Rett syndrome. Jaenisch and colleagues here provide an overview of our current understanding of the mechanisms by which MECP2 interacts with DNA and its diverse roles in gene regulation, and consider the implications of these insights for future therapeutic interventions.