A single faulty gene on the X chromosome can either silence or over-amplify a crucial brain protein, causing two devastating autism spectrum disorders. This research tackles a fundamental puzzle: how does the MeCP2 protein control brain function, and why do both too little and too much of it cause severe intellectual disability? Current theories disagree—some see MeCP2 as a jack-of-all-trades protein, while others argue it primarily acts as a genetic dimmer switch that represses gene activity. The team will test these competing ideas head-on, using genetically engineered mice and lab-grown human neurons to pin down exactly how MeCP2 binds to DNA and alters gene expression. If successful, the work could transform the outlook for Rett syndrome and MECP2 Duplication Syndrome—conditions that currently have no effective treatments. The researchers have already shown that Rett syndrome is reversible in principle; this project aims to turn that insight into actual drugs by designing small molecules that stabilise or correct the faulty protein. While the core work is fundamental science, clarifying MeCP2’s basic mechanism could also illuminate broader principles of how single-gene mutations disrupt neural circuits, potentially guiding future therapies for other autism-related disorders.
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Mutations in the MECP2 gene are responsible for two autism spectrum disorders (ASDs): Rett Syndrome[1] (loss of function) and MECP2 Duplication Syndrome[2] (over-expression). Involvement in monogenic ASDs has prompted intensive study of MeCP2 protein, but its functional role remains uncertain. As either too little or too much MeCP2 protein leads to profound intellectual disability, understanding how this protein contributes to brain function is a priority. A prominent view is that MeCP2 is a multifunctional hub protein implicated in diverse pathways. A simpler alternative, suggested by the restricted distribution of Rett syndrome (RTT)-causing mutations, is that MeCP2 is primarily a transcriptional repressor that binds methylated DNA[3] and recruits a co-repressor complex[4]. This research programme is designed to distinguish these hypotheses through a series of experiments that challenge each. It will use the resulting basic knowledge to develop small molecules that may be used therapeutically. The following component questions will be addressed: 1. What are the determinants of MeCP2 binding to chromatin in vivo? Although the protein has been shown to bind methylated DNA, additional determinants have been proposed. 2. Is the ability to bind both DNA and NCoR/SMRT sufficient for MeCP2 function? Our previous work suggests that these two discrete interaction domains are of over-riding functional importance for MeCP2 function. We will create mutations in mice that test this hypothesis. 3. How and why is gene expression affected by varying levels of MeCP2? The reported effects of MeCP2-deficiency on brain gene expression are inconsistent, rangingfrom no clear effects, to mostly activation or mostly repression[5]. We will use homogeneouspopulations of cultured human neurons to resolve this question. 4. Can we identify therapeutic options for treatment of Rett syndrome and MECP2 Duplication Syndrome? Our earlier work established proof-of-principle that Rett syndrome is a reversible condition and therefore in principle curable[6]. So far, however, there are no effective treatments for any MeCP2-related condition. Based on our molecular insights into thebiochemical consequences of specific Rett mutations, we will collaboratively seek small molecules that stabilise or disrupt the structure/interactions of wildtype and mutant MeCP2.
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