Opposing Nucleotides

Several years ago, scientists in the laboratory of HHMI investigator Nathaniel Heintz discovered high levels of an unusual molecule called 5-hydroxymethylcytosine, or 5hmC, in brain cells. Its function was unknown, but new research by Heintz and his colleagues hints that it may play a role in the neurological disorder Rett syndrome.

Huda Zoghbi discusses Rett syndrome and its causes.

5hmC is a modified form of cytosine—one of the four DNA building blocks. Intrigued by its abundance in brain cells, Heintz’s team at the Rockefeller University began mapping where the nucleotide occurred in the genome. They also identified locations of another modified version of cytosine, 5-methylcytosine, or 5mC. The resulting map revealed that 5hmC was most plentiful in active genes, while large amounts of 5mC appeared in inactive, or silent, genes.

A search for molecules that bind to 5hmC turned up only one candidate—MeCP2, a regulatory protein that is mutated in Rett syndrome. As the team reported December 21, 2012, in Cell, tests showed that MeCP2 binds 5hmC and 5mC with equal affinity and that binding to 5hmC is associated with active transcription.

Heintz hypothesizes that the two modified forms of cytosine are responsible for different aspects of the disease. He plans to investigate how the same MeCP2 protein can trigger these opposing effects, depending on which nucleotide it binds.

Scientist Profile

The Rockefeller University
Molecular Biology, Neuroscience

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