The expression of genes is titrated precisely to achieve the proper balance of functions in all human tissues, including the brain. Ratcheting expression up or down is orchestrated by proteins that bind to DNA, leading to suppression or activation of gene function, but it also depends on signals left on chromosomes, including chemical modifications of the DNA itself. Adrian Bird devised a method for mapping one such chemical mark along chromosomes, namely the presence of a methyl group on the cytosine residue in DNA. This revealed a pattern of methylated and non-methylated sites that helps demarcate genes that can be switched on from those that are to remain silent. One way that this works emerged from his discovery in the 1990s of five different proteins that depend on methylation for their binding to DNA and can silence genes. One member of the protein family, MeCP2, recruits a large complex of enzymes that chemically alter chromosome marks by removing an acetyl chemical tag from a major structural component of the chromosome known as histones. The inter-connection of these two chemical features – the presence of methylcytosine in chromosomal DNA and the loss of acetyl groups on histones – establishes ‘epigenetic’ marking of chromosomal regions causing gene activity to be turned down.
The basic molecular mechanisms uncovered by Bird’s research acquired new significance through completely independent work on a seemingly unrelated biological problem. Huda Zoghbi, a pediatric neurologist studying genetic disorders associated with developmental delay and intellectual disability, made an unexpected connection between one of Bird’s methyl-cytosine-binding proteins, MeCP2, and a challenging neurological disorder called Rett syndrome.