Mini model: Fruit flies have fewer genes than people do, but carry versions of 75 percent of human disease-causing genes. 

Mini model: Fruit flies have fewer genes than people do, but carry versions of 75 percent of human disease-causing genes. 

A new study reveals the three-dimensional structure of fruit fly chromosomes, which groups together active and inactive genes. The results were published 3 February in Cell¹.

Not long ago, gene expression was believed to be essentially linear, with regulatory regions controlling the expression of adjacent genes. DNA is now known to wrap around a structure called the nucleosome, which fine-tunes gene expression by altering how tightly the molecule is wound.

The new work provides a glimpse at yet another level of gene regulation: the organization of chromosomes in three-dimensional space.

The fruit fly genome, although much smaller than that of humans, contains versions of about 75 percent of genes involved in human disease. For example, researchers have learned about both fragile X syndrome and autism by studying mutant flies that model these disorders. 

In the new study, the researchers constructed a genome-wide map of chromosomal structure in fruit flies.

They treated the chromosomes with a chemical that preserves their three-dimensional shape, and then used an enzyme to chop up the DNA molecules at a specific sequence of nucleotides, the building blocks of DNA. Finally, they fused these fragments together, allowing the DNA to bond not just to where it was cut, but also to nearby clusters, creating chimeric, or hybrid, sequences.

By sequencing more than 362 million of these chimeras, the researchers were able to create a picture of the proximity of different genetic regions when DNA is tightly packaged into chromosomes.

Chromosomes are folded into distinct domains that are separated by insulator proteins. These proteins form a physical barrier between regions harboring genes with different levels of expression, the study found. Each of these domains is characterized by a specific pattern of histone modifications, which are chemical alterations to nucleosomes that change the way they interact with DNA.

For example, genes with the H3K4 trimethyl mark, which is known to activate gene expression, cluster together in domains that primarily contain active genes. Other regions group together genes with histone marks that turn off expression, such as H3K27 trimethyl.

Modifying gene expression in this way, without changing the underlying DNA sequence, is called epigenetics. Researchers are beginning to understand the function of epigenetics in disease, and the role it is likely to play in regulating the complex gene-environment interactions that underlie autism.

Understanding how chromosomes are organized in fruit flies provides a basis on which to begin to understand this level of epigenetic regulation in other organisms and in disease, the researchers say.

References:

1: Sexton T. et al. Cell 148, 458-472 (2012) PubMed