Scientists identify a possible molecular mechanism of Rett syndrome

Researchers have found a new molecular role for MeCP2, the protein that doesn’t work correctly in people with Rett syndrome. The findings could suggest new ways to treat the neurodevelopmental condition, the scientists say.

Rett syndrome is a genetic condition that mainly affects girls, and usually becomes apparent in children 6–18 months old. Those children with the syndrome regress developmentally, and lose motor control and the ability to speak. In 1999, Huda Zoghbi at the Baylor College of Medicine and colleagues determined that the disorder was caused by mutations in the gene coding for the protein MeCP2.

Ali Hamiche at the Institute of Genetics and Molecular and Cellular Biology in Strasbourg and his group found the new role for MeCP2 while investigating methylated and hydroxymethylated cytosine and adenosine repeats in DNA (CACACACACA, and so on). The group was looking for proteins that bind or interact with these genetic elements to understand how these sequences affect gene regulation. To the group’s surprise, Hamiche says, they found that MeCP2 binds these repeating sequences (Science 2021, DOI: 10.1126/science.abd5581).

Hamiche and his colleagues then teamed up with structural biologists and used X-ray crystallography to observe how mutated and nonmutated versions of the protein bind to DNA. The scientists found that when MeCP2 without Rett-related mutations binds to specific CA repeats, it changes the DNA structure. This change prevents DNA from being wrapped up into nucleosomes. In contrast, mutated MeCP2 proteins can’t bind the CA repeats and, as a result, these repeat regions have many more nucleosomes and end up much more tightly packed. This tight packing could potentially change the regulation of genes along that stretch of DNA.

In a commentary accompanying the new paper, Zoghbi explains that the findings back up previous evidence that MeCP2 is involved in the organization of chromatin, the cellular material consisting of DNA wrapped into nucleosomes. But Qiang Chang, who researches MeCP2 at the University of Wisconsin, Madison, says that the relevance of this newly discovered function for MeCP2 to Rett syndrome remains to be proven. MeCP2 has other functions in addition to DNA binding and more research is needed to show that this wrapping mechanism happens in the neurons of people with Rett syndrome and how it leads to the neurodevelopmental effects of the disease.

Hamiche hopes the team’s new findings can help in the search for a treatment. His team continues to work on how exactly MeCP2 affects chromatin reorganization and nucleosome binding.