Discovery will aid identification of misregulated genes in Rett Syndrome

Adrian Bird of the University of Edinburgh and colleagues report today in the online issue of Molecular Cell that the “Rett Syndrome protein”, MeCP2, only binds to genes with a specific sequence of nucleotide bases. This knowledge will aid in the identification of the genes that are regulated by the gene MECP2. This work was supported, in part, by the Rett Syndrome Research Foundation (RSRF).

Rett Syndrome (RTT) is a severe neurological disorder diagnosed almost exclusively in girls. Children with RTT appear to develop normally until 6 to 18 months of age, when they enter a period of regression, losing speech and motor skills. Most develop repetitive hand movements, irregular breathing patterns, seizures and extreme motor control problems. RTT leaves its victims profoundly disabled, requiring maximum assistance with every aspect of daily living. There is no cure.

The instructions needed to make the cells of all living organisms are contained in their DNA, which is organized as two complementary strands with bonds between them that can be “unzipped” like a zipper. DNA is encoded with building blocks called bases which can be abbreviated A, T, C, G. Each base “pairs up” with only one other base: A-T, T-A, C-G, G-C create the bonds that connect the complementary strands. Long stretches of base pairs make up genes.

All genes found in the human body are present in every one of our cells. What allows the same cells to develop into a heart in one instance and a kidney in another? The answer is gene expression. In a typical human cell only one tenth of the genes are expressed; the rest are shut down.

One way that genes are shut down is by attaching a small “tag” called a methyl group to the C base. The number and placement of the methyl tags dictates when a gene should be silenced. The protein, MeCP2, binds to these methyl groups to silence particular genes.

Dr. Bird and colleagues found that the methyl groups alone were not enough to attract MeCP2 to a gene. In fact, what is needed is a stretch of at least four A-T bases flanking the methyl groups.

“We previously thought that MeCP2 only needed methyl groups to bind DNA. As there are about 30 million such sites in the genome, it seemed likely that MeCP2 was a rather indiscriminate repressor of gene expression all over the genome. The new data shows that the number of potential MeCP2 binding sites is in fact far less than we thought, making it easier to find new target genes that are mis-regulated in Rett Syndrome,” said Adrian Bird.

Researchers hypothesize that the devastating cascade of symptoms seen in Rett Syndrome is caused by the inability of mutated MeCP2 to silence its target genes. To date, the genes DLX5 and BDNF have emerged as strong MeCP2 target candidates and are therefore implicated in the disease process of Rett Syndrome. Interestingly, both genes were found to have the required A-T stretch, strengthening the argument that MeCP2 is involved in regulating these genes.

“Finding the MeCP2 target genes is a crucial step in understanding what goes awry in Rett Syndrome. Unfortunately these genes have been elusive. Dr. Bird’s discovery of the A-T stretch provides a much-needed clue which should aid in their identification,” said Monica Coenraads, Director of Research for RSRF.