Genes that are activated during red blood cell differentiation (green and red) cozy up in a human erythroblast.

Active genes can be sociable, snuggling up to one another. Brown et al. offer a new explanation for this clustering, suggesting that genes gather for the services of RNA splicing enzymes

A gene's location in the nucleus often reflects its activity. Hard-working genes tend to congregate in the interior of the nucleus, whereas their lazier counterparts hang out at the edge. Moreover, active genes on different chromosomes sometimes bunch up. How often active genes come together is uncertain. Whether the associations serve a purpose is also unclear, although some researchers propose that genes converge at so-called transcription factories that contain RNA polymerase.

To address these issues, Brown et al. pinpointed five genes that crank up during the differentiation of human red blood cells. Some of the genes were friendlier than others. For example, two α-globin genes were about five times more likely to be near each other than were two β-globin genes.

Next, the researchers tested whether a gene's chromatin environment affects its tendency to cluster. In human cells, β-globin sits in a tightly packaged chromatin region, whereas α-globin's neighborhood is looser. But in mouse cells, α-globin resides in a condensed region. The team replaced the mouse α-globin gene with the human version, so that the ordinarily loose human gene was now in a condensed chromatin environment. Like the β-globin gene in human cells, the inserted α-globin gene in mouse cells was aloof, suggesting that a gene's surroundings do influence its position relative to other genes. However, the team found that the inserted gene worked normally, showing that associations aren't essential for normal transcription.

The results also indicate that genes aren't sharing transcription factories. The average distance between associating active genes, the researchers determined, was about 10 times the diameter of a factory. Instead, the genes were congregating at nuclear speckles, much larger structures than factories that harbor enzymes for splicing RNA after transcription. The team concludes that genes associate because they sometimes happen to be drawn to the same speckle.

Brown, J.M., et al.
J. Cell Biol.