Knockout yields clues to how sperm are perfected for penetration.

The round, dense head of a mature sperm allows it to penetrate the outer layer of an egg.

Examining mouse testes under a microscope, Yi Zhang couldn't find any mature sperm. But that was a good thing. It meant that knocking out a single gene, called Jhdm2a, in mice wrecked their ability to produce mature sperm.

The knockout had blocked “chromatin condensation,” a process critical for sperm maturation. Chromatin condensation entails replacing the protein packing material around the genes in a sperm's head with basic proteins—specifically, transition proteins and protamines—transforming maturing sperm from marshmallows into missiles. The resulting denser heads can slam into an egg with enough force to penetrate its outer layer, enabling fusion and fertilization.

HHMI investigator Zhang and his colleagues at the University of North Carolina at Chapel Hill published their findings online in Nature on October 18, 2007.

By showing that the Jhdm2a gene is necessary for DNA condensation in sperm, Zhang shed light on an important gene regulatory mechanism, called epigenetic control. Epigenetic modification alters histone proteins—the “smart stuffing” that DNA coils around within chromosomes. This alteration switches genes on or off. Genetic regulation, in contrast, depends on control sequences integral to the DNA molecule.

The Zhang group demonstrated that the Jhdm2a gene encodes an enzyme that removes methyl groups from histones and switches on associated genes. Jhdm2a activates genes that encode the transition proteins and protamines needed for condensation of sperm DNA. According to Zhang, the finding could have implications for treating infertility and for birth control.

“Many cases of human infertility arise from defects in sperm production,” he says. “While we have yet to demonstrate that this gene is important in human spermatogenesis, our findings raise the possibility that it might be. If so, remedying this defect could treat such infertility.

“On the other hand,” he adds, “because this gene is very specific to spermatogenesis, a drug that inhibits the enzyme could provide highly targeted male birth control.”

Photo: David M. Phillips / Photo Researchers, Inc.