In contrast to the scene in this colorized scanning electron micrograph, chromosomes in a cell's nucleus are snugly packed—and they aren't just rubbing elbows.

Studying how cells of the mouse immune system mature and differentiate, researchers at Yale University recently discovered a surprising strategy. HHMI investigator Richard Flavell and his team observed the first instance of genes from separate chromosomes coordinating their activities by touching each other.

The researchers studied helper T cells (T_H cells), which can develop into T_H1 or T_H2 cells that use slightly different tactics—turning on distinct groups of genes—to fight infections. The Yale researchers had previously found out that in T_H2 cells a master control element on chromosome 11—called the locus control region (LCR)—turns on three nearby but widely separated genes that encode interleukins (proteins the cells use to neutralize pathogens). With the aid of a recently developed method, called chromosome conformation capture, to map physical contacts between different regions of DNA, Flavell's group learned that the LCR orchestrates the activities of the three interleukin genes by actually contacting parts of all three genes.

At around the same time, the researchers noticed that early in development T cells produce small amounts of both the T_H2-specific interleukins and the T_H1-specific cytokine interferon-γ, whose gene lies on chromosome 10. (Cytokines are proteins that stimulate or inhibit the joint action of immune cells.) Because the interferon-γ and interleukin genes seemed to be regulated in concert, Flavell surmised that the LCR on chromosome 11 might somehow bind both its neighboring interleukin genes and the interferon-γ gene on chromosome 10. That was a bold hypothesis. "In the past, people have thought that chromosomes acted independently," says Flavell. But the hunch turned out to be right.

Using fluorescent-microscope-imaging techniques, the Yale researchers directly witnessed the predicted regions of chromosomes 10 and 11 come in contact during early T_H cell development and then move apart as the cells committed to their final fates as T_H1 or T_H2 cells. The work was published in the June 2, 2005, issue of Nature.

In the past, people have thought that chromosomes acted independently... But the hunch turned out to be right.

Although questions remain about how the chromosome contacts regulate gene expression, the Flavell team suspects that the LCR serves to escort genes to regions of the cell's nucleus that offer a favorable environment for gene activation. Given nature's inherent efficiency, they speculate that chromosome contacts will prove to be a general mechanism for coordinating the activity of genes.

Image: Biophoto Associates / Photo Researchers, Inc.