More evidence for genetic master-switches in junk DNA

The mists surrounding the mechanisms that switch genes on an off in higher organisms are beginning to clear, with a new study published today in Cell revealing previously unrecognised domains of chromosomes that are involved in regulating genes - even whole clusters of genes.

The study, led by Dr Brad Bernstein, of the Broad Institute of Massachusetts Institute of Technology, analysed two entire human chromosomes - 21 and 22 - and other regions of the human and mouse genomes, for domains in which genes were "open for business".

While genome projects have provided researchers with a comprehensive catalogue, map and DNA sequence of all human and mouse genes, they do not reveal which genes are active - or potentially active, in living organs and tissues.

The MIT team used Affymetrix GeneChip microarrays containing millions of distinct DNA fragments to examine chromatin, the complex mix of DNA, RNA and proteins that forms chromosomes.

Using a technique called CHIP on Chip (Chromosome ImmunoPrecipitation) on a chip, Bernstein and his colleagues dissected chromosomes 21 and 22 and used antibodies to label particular forms of histones, the core proteins around which DNA is coiled, to determine which regions of chromosomes were "open" or "closed" to the cell's gene-transcription machinery.

They found that much of the human genome is organised into small chromatin structures remarkably similar to those in budding yeast, that appear to regulate the function of individual genes.

But they also found 'striking exceptions': huge chromatin domains where clusters of genes are regulated in a coordinated manner - including the Hox gene cluster that lays down the basic body plan in organisms as diverse as fruit flies, mice and men.

The hox genes form a linear cluster on the chromosome, and are progressively switched in the same order, so the body plan, including the segmentation process, occurs in a precisely ordered manner.

Both the small and large chromatin structures are almost identical in humans and mice - even though the DNA sequences of the underlying genes are quite difference, indicating that the chromatin regulatory structures have important functions that have been highly conserved through nearly 100 million years of mammalian evolution.

Some of the tracts of non-protein coding DNA between the hox genes, like the genes themselves, are densely "labelled' with methyl molecules that regulate gene transcription - confirming that these regions, once dismissed as "junk" DNA, are extensively transcribed when the hox cluster is "open for business".

Commenting on the findings, Professor John Mattick, director of the Institute for Molecular BioScience at the University of Queensland, said the findings lend further support to his idea that the "junk" DNA actually codes for RNA elements that control the activity of genes in the region.

He said the intensive activity in the intergenic regions of the hox gene cluster is further evidence that the activity of the body-plan genes is highly coordinated.

"This is consistent with my idea that complex developmental processes in mammals involve RNA signalling sequences," he said. "The hox genes are critical master regulators of animal development, so they have to be controlled in an extremely sophisticated way."