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Study implicates new epigenetic player in mental retardation and facial birth defects
Date:7/12/2010

the twisting double-helix strands actually spool around clusters of proteins called histones with protruding "tails" that act like specialized antennas, transmitting directions for DNA. This dynamic structure, called chromatin, extends the genetic code by offering, measuring or limiting access to different genes.

Several years ago, Shi and his colleagues identified the first enzyme that can detach a molecule known as a methyl group, previously thought to be a permanent fixture, from the histones tails. Then his team and a number of other research groups independently discovered members of a second known family of these enzymes, known collectively as histone demethylases.

The latest study began with a gene mutated in several male patients with X-linked mental retardation and craniofacial abnormalities. The gene codes for an enzyme that looked a lot like a member of the second family of histone demethylases. The mutations in these patients abolished the working part of the enzyme that plucks the methyl group from the histone tail.

Led by Hank Qi, PhD, co-first author and postdoctoral fellow, the researchers demonstrated in human cells that the enzyme, PHF8, indeed works as a histone demethylase. (And it is the first known demethylase discovered for a strategic methylation point on the tail of histone 4 known as H4K20, which other evidence suggests plays a critical role in gene expression and regulation and in the DNA damage response.) In this case, by removing the methyl group, the enzyme appears to maintain active gene transcription.

"The histone methylation and demethylation doesn't turn the gene on or off," Qi says. "When this histone mark changes, it generates an equilibrium important for fine-tuning gene expression."

Despite its widespread presence, the enzyme seems to have a narrowly targeted biological effect on a master genetic regulator of craniofacial development, the transcription factor MSX1. Taking a cue from
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Contact: Erin McColgan
erin.mccolgan@childrens.harvard.edu
617-919-3110
Children's Hospital Boston
Source:Eurekalert

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