Adrian Bird of the University of Edinburgh and colleagues report todayin the online issue of Molecular Cell that the "Rett Syndrome protein",MeCP2, only binds to genes with a specific sequence of nucleotidebases. This knowledge will aid in the identification of the genes thatare regulated by the gene MECP2. This work was supported, in part, bythe Rett Syndrome Research Foundation (RSRF).
Rett Syndrome (RTT) is a severe neurological disorder diagnosedalmost exclusively in girls. Children with RTT appear to developnormally until 6 to 18 months of age, when they enter a period ofregression, losing speech and motor skills. Most develop repetitivehand movements, irregular breathing patterns, seizures and extrememotor control problems. RTT leaves its victims profoundly disabled,requiring maximum assistance with every aspect of daily living. Thereis no cure.
The instructions needed to make the cells of all livingorganisms are contained in their DNA, which is organized as twocomplementary strands with bonds between them that can be "unzipped"like a zipper. DNA is encoded with building blocks called bases whichcan be abbreviated A, T, C, G. Each base "pairs up" with only one otherbase: A-T, T-A, C-G, G-C create the bonds that connect thecomplementary strands. Long stretches of base pairs make up genes.
All genes found in the human body are present in every one ofour cells. What allows the same cells to develop into a heart in oneinstance and a kidney in another? The answer is gene expression. In atypical human cell only one tenth of the genes are expressed; the restare 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 themethyl 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 alonewere not enough to attract MeCP2 to a gene. In fact, what is needed isa stretch of at least four A-T bases flanking the methyl groups.
"We previously thought that MeCP2 only needed methyl groups tobind DNA. As there are about 30 million such sites in the genome, itseemed likely that MeCP2 was a rather indiscriminate repressor of geneexpression all over the genome. The new data shows that the number ofpotential MeCP2 binding sites is in fact far less than we thought,making it easier to find new target genes that are mis-regulated inRett Syndrome," said Adrian Bird.
Researchers hypothesize that the devastating cascade ofsymptoms seen in Rett Syndrome is caused by the inability of mutatedMeCP2 to silence its target genes. To date, the genes DLX5 and BDNFhave emerged as strong MeCP2 target candidates and are thereforeimplicated in the disease process of Rett Syndrome. Interestingly, bothgenes were found to have the required A-T stretch, strengthening theargument that MeCP2 is involved in regulating these genes.
"Finding the MeCP2 target genes is a crucial step inunderstanding what goes awry in Rett Syndrome. Unfortunately thesegenes have been elusive. Dr. Bird's discovery of the A-T stretchprovides a much-needed clue which should aid in their identification,"said Monica Coenraads, Director of Research for RSRF.
Founded in late 1999, RSRF is the world's leading private funder ofbiomedical research for Rett Syndrome. For more information on RettSyndrome or the Foundation please visit our website at www.rsrf.org
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