Genetic basis for gender differences in the liver

Scientists at the University of Michigan Medical School have identified two genes responsible for an important, yet often overlooked difference between the sexes.

One of the less evident physiological differences between males and females resides in the liver. Male and female livers express different subsets of genes, which affect the organ’s ability to metabolize certain drugs and hormones. This in turn impacts numerous processes, such as reproduction. While the sexual dimorphism of the liver has been recognized for several decades, scientists are only recently beginning to uncover the genes involved.

In the November 1 issue of Genes & Development, Dr. Diane Robins and colleagues report on their discovery of two neighboring genes, Rsl1 and Rsl2, that repress male-specific liver gene expression in female mice. They found that female mice harboring mutations in Rsl genes aberrantly turn on male-specific liver genes, causing the female livers to adopt characteristically male patterns of gene expression.

According to Dr. Christopher Krebs, first author of the study, “Using genetic tools, we set out to clone Rsl because of its role in establishing gender differences in liver function, particularly in drug metabolism. Instead of just one gene, we discovered a huge cluster of related genes. To our surprise, it takes a pair of these genes to restore normal liver gene expression to mutant mice.”

Interestingly, the researchers note that the Rsl genes appear to function through a division of labor, with each regulating a subset of male-specific genes. While these genes appear to share the control of normal hepatic gene expression, under some circumstances one may be able to compensate for defects in the other.

Dr. Robins and colleagues determined that Rsl1 and Rsl2 belong to a large family of structurally related genes, called the KRAB-ZFP gene family, with over 200 members in the mouse and human genomes. Although biochemical work has suggested a role for KRAB-ZFPs in gene silencing, this current study provides the first functional role for any KRAB-ZFP in vivo.

Dr. Robins suggests that these genes may be most interesting from an evolutionary perspective. “This gene family has arisen recently in evolution, and diversified rapidly, but the way they act is highly conserved. Since Rsl regulates genes at puberty that are involved in reproduction and hormone metabolism, it may be that not only Rsl, but also other members of the KRAB-ZFP family, influence functions that lead to speciation.”