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.

Rett syndrome was first described by Andreas Rett in 1966 as a distinct but oddly variable neurobehavioral condition in females. The disease affects approximately 1 in 10,000 girls who show normal development for 6 to 18 months, but as the disease takes hold, they become withdrawn, regress in their mental development, exhibit compulsive behavior such as incessant hand-wringing, and eventually lose all purposeful use of the hands. What made Rett difficult to understand was that it was usually sporadic, appearing out of the blue in an otherwise healthy family. But because Rett is mainly seen in females, and only very rarely in families where there had been early loss of male children, Zoghbi suspected it to be caused by an X-linked mutation that is lethal in males. In 1999, after 15 years of scrutinizing the genome, Zoghbi and colleagues discovered that mutations in MECP2 are the primary cause of Rett syndrome. Her discovery allowed a confusing set of symptoms to be turned into a straightforward diagnostic genetic test. Mutations in MECP2 are now known to cause a variety of neuropsychiatric features ranging from autism to juvenile-onset schizophrenia.

The Zoghbi and Bird groups independently produced different genetic mouse models of Rett syndrome that reproduced the major symptoms of the disease. In dramatic contrast to the irreversible damage associated with many neurologic disorders, however, Bird’s group demonstrated that the animal model of Rett Syndrome could be restored to normal by reintroducing a functional copy of MeCP2 in adult animals, even though they were already symptomatic. His group also found that the MeCP2 protein is quite abundant in nerve cells, approaching the level of the major chromosome-binding histones; a change in MeCP2 function is thus likely to have a profound affect on chromosome structure in the brain. Zoghbi’s group showed that MeCP2 is critical for the normal function of many different types of neurons and that the brain is sensitive to relatively modest increases or decreases in the levels of MeCP2. In fact, doubling MeCP2 levels causes a progressive neurological syndrome in mice that is every bit as severe as Rett syndrome. These observations led to identifying MECP2 as the culprit in children with large duplications spanning the gene in Xq28. MECP2 Duplication Syndrome, which primarily affects male children, is now known to account for about 1% of cases of intellectual disabilities and autism. The Zoghbi lab was able to reverse this disorder in adult duplication syndrome mice by using antisense oligonucleotides (ASOs) to normalize MeCP2 levels.

These discoveries showed the profound importance of epigenetics to neurobiology and now suggest a path to treatment of certain neurologic disorders using the emerging technology of gene editing and ASOs. These highly complementary studies show, once again, the power of basic science to uncover the fundamental basis of human development and disease.

27 September 2016   Hong Kong