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New Method Developed to Study MeCP2 Function in Humans

We wanted to share with the RSRT community a little about a new method we’re using to gain a better understanding of how the MECP2 protein functions. Our expectation is that this research, which is funded by RSRT and the NIH, will help guide approaches to therapeutics that will hopefully change the lives of all who struggle with Rett Syndrome. We hope our words here reflect our enthusiasm for the work we do, and the gratitude we have to RSRT and all its supporters.

Over the nearly 30 years since Dr. Adrian Bird’s laboratory discovered MeCP2, researchers have learned a great deal about how this protein works. These discoveries have largely relied on genetically engineered mice and cultured cells because it has not been feasible to directly study MeCP2 function in humans. One of the main reasons that studying MeCP2 in humans has been difficult is because girls with Rett Syndrome have a mixture of cells that express either mutant or normal MeCP2 within their brain, and there has not been a way to easily distinguish between them. In our recent Nature Neuroscience paper, we developed a new approach to overcome this challenge, enabling the direct study of MeCP2 function in autopsy brain tissue from individuals with Rett Syndrome.

Our new approach for studying gene expression abnormalities in Rett leverages advances in single-cell sequencing technology to determine which cells express mutant or normal MeCP2. We then compared mutant and normal cells within the same brain tissue from donors who had Rett Syndrome caused by R255X mutations in MeCP2. We observed that genes that contained high levels of DNA methylation and were very long were significantly upregulated when MeCP2 is mutated, an effect that has also been observed in cell lines and mouse models. This conserved molecular signature of Rett Syndrome gives us clues about how MeCP2 functions and ways we might be able to overcome its mutation in human neurons.

By studying brain cells individually rather than mixing them together as we used to do prior to single-cell sequencing, we observed that MeCP2 mutations lead to the misregulation of different gene programs in different types of neurons within the same individual. We still do not know, however, which of these genes are directly controlled by MeCP2 and which are changed because of adaptations many steps removed from MeCP2’s direct function. Because gene expression changes in MeCP2-mutant cells are different in each cell type, our best chances to reverse Rett Syndrome outside of gene therapy may be to focus on MeCP2’s most direct function, which is likely to be shared across all cell types, rather than the numerous and variable secondary consequences of MeCP2 mutations. Ongoing studies in the lab are focused on better understanding these direct mechanisms of MeCP2 that are common across cell types in hopes of guiding novel therapeutic design.

This research was funded by RSRT and NIH.