These models help to highlight the key functions of MeCP2 as binding to DNA and association with another protein complex, called NCoR, that reduces expression of genes. They also show that the level of MeCP2 protein is crucial and may be a key determinant of disease severity. MeCP2 may have many other functions in the brain, but these seem essential in relation to Rett syndrome.
A knockout model simply removes MeCP2 protein. This does not reflect the situation in girls with Rett syndrome where the mutant protein is still present. Knockout models have been important in Rett syndrome research, but haven’t explained exactly what MeCP2 does or why Rett syndrome is the result when it is mutated. The mutation specific models are more clinically relevant and allow us to pinpoint regions of the protein that are necessary for particular functions and gain insight into the reason why one girl with Rett syndrome caused by a particular mutation might have a less severe clinical picture than one with another mutation.
The MeCP2 protein carried a fluorescent tag so that, in the lab, we can visualize its localization in the nucleus and measure binding to DNA more easily.
It was previously suggested that the R133C mutation in MeCP2 results in a specific loss of protein binding to DNA that is hydroxymethylated. This type of DNA modification has been associated with active genes. We now know that MeCP2 does not bind to the most abundant form of hydroxymethylated DNA in the brain and our paper shows that MeCP2 with the R133C mutation does not bind normally to other forms of modified DNA (methylated, associated with inactive genes), so there is no specific loss of binding to hydroxymethylated DNA.
Some info on who Kyla and Jim are:
I am a doctor, specializing in Child and Adolescent Psychiatry. I am interested in neurodevelopmental disorders like Rett syndrome. I came to the Bird lab as part of a Wellcome Trust funded clinical PhD fellowship organized by the University of Edinburgh’s Clinical Academic Training Scheme that lasted for three years.
I have worked in The University of Edinburgh for over 25 years, during which time much of my career has focused on generating mouse models of human disorders. It was this expertise that brought me to the Bird lab where I have spent more than 12 years generating and studying mouse models of Rett.