Researchers at the University of Penn School of Medicine have created a new mouse model that enabled them to identify defects in the sperm epigenome that cause male infertility.
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The development, which was recently described in the journal Developmental Cell, could lead to new ways of correcting defective sperm.
One in eight couples has difficulty conceiving
One in eight couples has difficulty conceiving, and in almost 25% of those cases, the underlying problem is male infertility. Research over the last ten years has attributed this infertility to faulty sperm that do not "evict" histones from DNA during development. Histones are the proteins in chromatin that package DNA, switch genes on and off, and replace them with much smaller proteins called protamines that are able to package DNA into sperm properly.
However, researchers have not fully understood the mechanisms underlying this eviction or where exactly they take place in the sperm DNA.
Now Penn Medicine researchers Lacey Luense, Shelley Berger, and Daniel Och have used new genome-wide DNA sequencing techniques to find precisely where the histones are retained in the genome and identified an important gene called Gcn5 that regulates the process.
They then engineered a mouse model with a mutated version of Gcn5, which enabled them to closely monitor defects from the early phase of sperm development through fertilization and onwards.
An important development
This important development could not only improve understanding of male infertility and potential ways to reverse it but, but also the epigenetic mutations that may get passed onto an embryo from the male.
Epigenetics, the heritable changes in the genome that are not encoded for by DNA, strongly influence how the sperm are formed. "For men who have unexplained infertility, everything may look normal at the doctors: normal semen counts, normal motility. Yet they can still have problems conceiving," says first author Luense.
Luense says one potential explanation is histones being in the wrong place, 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."
Given the understanding that retained histones influence fertility and embryonic development, scientists are interested in identifying their genomic locations so they can potentially be used for future research and, eventually, the development of treatments.
Previous research has generated conflicting results
Previous studies have generated conflicting results. Some research using a technology called MNase-sequencing has determined the location of retained histones as on important gene promotors, while other research using the same tool, has identified them at DNA repeats and in so-called "gene deserts," where they are less involved in regulation.
The current study suggests both models are correct
These discrepant data have led to controversy among researchers in the field, says Luense. However, the current study suggests that both of the models described are, in fact, correct.
We find histones on genes that appear to be important for embryo development, but we also find them at repetitive elements, places that do need to be turned off and to prevent expression of these regions in the embryo."
Penn Medicine researcher, Lacey Luense
For the study, the team used a newer, faster, and more precise technology called ATAC-sequencing to track histones at unique sites across the genome throughout the early and late stages of sperm development in mice. This approach can identify genomic regions where histones are retained and then cut and tag that DNA so that it can be sequenced.
The researchers found that the mice engineered to have mutated Gcn5 had very low fertility. They also found that histones retained in healthy sperm correlated with the position of histones in very early embryos, which supports the thinking that epigenetic information is passed on by paternal histones.
An opportunity to investigate potential treatments
Using the mutant model, researchers can study in detail the mechanisms underlying the defective sperm's trajectory and what effect that might have on embryonic development. It also provides an opportunity to investigate potential therapeutic targets.
Berger points out that, currently, the burden of IVF and other assisted-reproductive technologies falls on women and that even if infertility is due to male factors, it is still women who have to go through hormone injections and procedures.
"Now imagine being able to apply epigenetic therapeutics to change the levels of histones and protamines in males before embryogenesis?" she says. "That's one of the questions we want to explore, and this model will allow us to move toward that direction."
The team says limitations with human embryos have led to a lack of overall research on infertility and the role of the father's epigenome on embryonic development, which highlights the importance of studies such as this.
"There are a lot of different factors that can alter the sperm epigenome: diet, drugs, alcohol, for example," says Luense. "We are just now starting to understand how that can affect the child and affect development. These initial, basic studies that we are doing are critical, so we can better understand what's driving these epigenetic mutations."
Penn researchers uncover defective sperm epigenome that leads to male infertility. EurekAlert. Available from https://www.eurekalert.org/emb_releases/2019-12/uops-pru121319.php