Wednesday, October 24, 2007

Study Shows Protein Linked to Male Infertility - Implications for Potential Birth Control Drug

Picture the healthy sperm. Valuable DNA stored in the head is propelled by a powerful tail on the quest to create life bigger than itself. Once the sperm reaches the egg, a battle of strength and strategy ensues. The egg is protected by a tough outer shell which the sperm must penetrate. If the sperm is successful in breaking through that barrier, cellular union and division begin, creating the magic of new life.

But what if the sperm isn't powerful enough to break through the shell? What if the sperm has the density of, say, a water balloon or a bag of sand? What if the mighty sperm doesn't possess the force of a battering ram?

For sperm to become a battering ram, it must "compress into a tight ball before springing into action." In the nucleus of the sperm cell, strands of DNA are wrapped around spools of protein called histones. Chemical tags, such as methyl groups affixed to the histones, govern how tightly the DNA can be compacted.

Scientists at the University of North Carolina at Chapel Hill have identified a gene crucial to the sperm's ability to "scrunch up tightly enough" to penetrate the egg. In this study, mice genetically engineered to lack this crucial gene had smaller testes, a significantly lower sperm count, and were infertile. In addition, the few sperm that were produced by these mutant mice displayed significant morphological defects, including abnormally shaped heads and immobile tails.

"In order for sperm to be able to enter the egg, the sperm chromatin has to be tightly packaged," said Yi Zhang, Ph.D., Howard Hughes Medical Institute investigator and professor of biochemistry and biophysics in the UNC School of Medicine. "It must become like a dense ball, so that when it hits the egg, it can penetrate. And in order for this DNA to be tightly packaged, the histone proteins must be replaced by other basic proteins."

In their experiments, Zhang and his colleagues explored the function of the enzyme Jhdm2a which is a histone demethylase. Histone demethylase enzymes activate genes by snipping molecules called methyl groups from histones. Histone proteins make up the "smart stuffing" in chromosomes-the core of proteins around which the DNA winds so that it is packaged compactly.

The research team, led by Howard Hughes Medical Institute investigator Yi Zhang, published its findings online in Nature on October 18, 2007. Zhang and his colleagues at UNC collaborated on the studies with researchers in the Laboratory of Reproductive and Developmental Toxicology at the National Institutes of Health. The research was funded by the Howard Hughes Medical Institute and the National Institutes of Health.

The researchers focused on the function of Jhdm2a because earlier studies had indicated that the gene for this protein is highly active in the testis and that Jhdm2a protein levels are highest during sperm maturation. The studies show that if this key protein is missing, the genetic material, called chromatin, does not condense normally, a process which is necessary for fertilization to be successful.

Zhang said that although their study was done in mice, it might well have implications for understanding some forms of human infertility. "Because this gene has a very specific effect on the development of functional sperm, it holds great potential as a target for new infertility treatments that are unlikely to disrupt other functions within the body."

Drugs that affect the Jhdm2a enzyme might have clinical use. "A small molecule that enhances the enzyme's activity could be a useful fertility drug in cases where compromised function of the gene has caused infertility," Zhang said. "On the other hand, a small molecule that inhibits the enzyme's activity could be a potential birth control drug."

Zhang and his colleagues are now looking for mutations in this gene in infertility patients, and are also interested in identifying the partners or cofactors in the cell that help this gene do its job. "Although a number of histone demethylases have been identified, very little is known regarding their biological functions, particularly in the context of whole animals," said Yuki Okada, Ph.D., a postdoctoral fellow in Zhang's laboratory and lead author on the study.

Study co-authors include Greg Scott, Manas K. Ray and Yuji Mishina from the National Institute of Environmental Health Sciences.

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