MeCP Protein’s Ability to Interact With DNA May Be Crucial for Brain Health
MeCP2, the protein missing or defective in most people with Rett syndrome, contains a specific domain it can use to interact with different sets of DNA building blocks found in gene sequences to control their activity.
After replacing the protein’s domain to prevent it from binding to a specific set made up of three nucleotides (DNA building blocks) in mice, scientists found signs of what would be a severe form of Rett in the animals, indicating that MeCP2’s binding to such gene sequences is needed to maintain normal brain function and avoid disease onset.
Their study, “Neuronal non-CG methylation is an essential target for MeCP2 function,” was published in the journal Molecular Cell.
Rett syndrome is characterized by the lack of a functional version of MeCP2, a protein that is known to control the activity of other genes.
Originally, MeCP2 was found to be able to suppress gene transcription — the process by which a gene’s DNA sequence is converted into RNA that will then be used by cells as a template to make a protein. It does so by binding to pairs of methylated cytosine and guanine (mCG) nucleotides, and then recruiting other molecules to prevent transcription. (Methylation is a chemical change in which a methyl group is added to the DNA sequence of a gene.)
More recently, it was discovered that MeCP2 can also suppress gene activity by binding to other groups of methylated nucleotides, including a set of three made up of cytosine, adenine, and cytosine (mCAC), which are often found in neurons.
Yet, it is often “difficult to disentangle the influence of mCG versus mCAC on the regulation of gene expression [activity] by MeCP2, as these marks are interspersed with one another,” the investigators noted.
Researchers in the U.K. used molecular genetic approaches to analyze their relative importance and effects on MeCP2 function.
They created a modified version of MeCP2, in which the protein’s dual DNA binding domain was swapped with an identical one from a different protein, called MBD2, that is only able to interact with mCG DNA sites.
After creating this alternative version of MeCP2, which they called MM2, the researchers inserted the new protein into mice to study its activity and function in a living body.
Their experiments showed that mice with MM2 developed several features typically seen in mouse models of Rett, including lack of activity with disease progression, and poorer motor coordination and motor learning skills, accompanied by weight loss.
“We conclude that binding to mCG alone is insufficient for MeCP2 to fulfill its role in the maintenance of neurological function,” the investigators wrote.
As in animal models of Rett, MM2 mice were born healthy and only started showing signs of the disease after weaning. This delay in the onset of Rett-like symptoms in MM2 mice may be explained by the accumulation of mCAC sites in terminally differentiated neurons, which only takes place following the animals’ birth, the team stated.
Results also showed that the protein’s inability to bind to mCAC sites in MM2 mice had consequences at a molecular level. The investigators discovered these animals had a series of dysregulated genes, many of which (around a third) were also found to be altered in mice genetically engineered to be unable to produce MeCP2, a well-established model of Rett.
Researchers also found that many of the genes dysregulated in both animal models had previously been associated with other neurological disorders, “potentially highlighting targets of relevance to the Rett syndrome phenotype [symptoms],” they wrote.