One out of eight couples has trouble conceiving, with nearly a quarter of those cases caused by unexplained male infertility. For the past decade, research has linked that infertility to defective sperm that fail to “evict” proteins called histones from DNA during development. However, the mechanisms behind that eviction and where this is happening in the sperm DNA has remained both controversial and unclear.
Now, researchers at Penn Medicine show, using newer genome-wide DNA sequencing tools, the precise genetic locations of those retained histones, as well as a key gene regulating it. The findings were published in Developmental Cell.
Taking it a step further, the researchers created a new mouse model with a mutated version of the gene, Gcn5, which allows investigators to closely track the defects in sperm from the early stages of sperm development through fertilization and on. This is an important step forward as it could lead to a better understanding of not only infertility in men—and ways to potentially reverse it—but also the suspected epigenetic mutations being passed onto the embryo from males either naturally or through in vitro fertilization.
Epigenetics, the factors influencing an organism’s genetics that are not encoded in the DNA, play a strong role in sperm and egg formation.
“For men who have unexplained infertility, everything may look normal at the doctor’s: normal semen counts, normal motility. Yet they can still have problems conceiving,” says first author Lacey J. Luense, a research associate in the lab of the study's senior author, Shelley L. Berger, the Daniel S. Och University Professor in the departments of Cell and Developmental Biology in the Perelman School of Medicine and Biology in the School of Arts and Sciences, and director of the Penn Epigenetics Institute. “One explanation for persistent problems is histones being in the wrong location, which may affect sperm and then early development. Now, we have a really good model to study what happens when you don’t get rid of the histones appropriately in the sperm and what that may look like in the embryo.”
Read more at Penn Medicine News.
