Researchers have long been puzzled by the protein MeCP2, which plays a critical role in brain development and is implicated in the neurological disorder Rett syndrome. A recent study from Rockefeller’s Shixin Liu’s laboratory sheds light on how MeCP2 interacts with DNA and chromatin, providing valuable insights into its function. The study, published in Nature Structural & Molecular Biology, could pave the way for new therapies for Rett syndrome.
Using a single-molecule approach, Liu and his team investigated how MeCP2 interacts with DNA. They found that MeCP2 moves differently on methylated and unmethylated DNA, allowing it to recruit other regulatory proteins more efficiently to methylated DNA sites. This discovery provides a deeper understanding of how MeCP2 differentiates between the two types of DNA. The team also discovered that MeCP2 has a strong preference for binding to nucleosomes, which are protein spools wound with genetic material. This interaction with nucleosomes may suppress gene transcription, shedding light on how MeCP2 regulates gene expression.
The findings from this study suggest that scientists may need to rethink the role of nucleosomes in gene regulation. Instead of being seen as inert “storage spools” of DNA, nucleosomes could play an active role in gene regulation, with MeCP2 functioning as a chromatin-binding protein. The team also identified the part of MeCP2 responsible for its nucleosome-binding activity, further elucidating its function. This new perspective on nucleosomes could open up new avenues for understanding gene regulation and the role of MeCP2 in diseases like Rett syndrome.
Moving forward, Liu and his team plan to expand their study to examine MeCP2 in vivo, where interactions with nucleosomes are expected to be more complex. They also aim to use the techniques described in the study to investigate the many MeCP2 mutations that cause diseases such as Rett syndrome. By gaining a more comprehensive understanding of MeCP2 and its role in Rett syndrome, researchers hope to develop effective therapies for this devastating disease. The study highlights how basic research can help the clinical community better understand and treat neurological disorders like Rett syndrome.
Overall, the study offers valuable insights into the intricate workings of MeCP2 and its interactions with DNA and chromatin. By utilizing a single-molecule approach, Liu and his team were able to uncover new details about how MeCP2 moves on DNA and its preference for binding to nucleosomes. This information could lead to new therapeutic strategies for diseases like Rett syndrome and advance our understanding of gene regulation. The researchers plan to continue their investigations to further elucidate the role of MeCP2 in neurodevelopment and diseases like Rett syndrome, paving the way for new treatments and therapies in the future.