Courtesy of Dr. Mia Levine
Gestation has traditionally been viewed as the mother’s domain, with dad doing little more than depositing his half of the genome. Now, a new study in fruit flies pinpoints a protein in sperm that regulates embryos’ earliest cell divisions.
Evolutionary biologists at Fred Hutchinson Cancer Research Center published a study Tuesday in the journal eLife showing that when dad flies are missing this protein, known as HP1E, fertilized eggs die before they can even hatch. The findings could point to new ways to study fertilization in humans and other animals.
In most cells of the body, be they fruit fly or human, DNA is packaged by a special set of proteins into an organization system known as chromatin. Think of chromatin as your cellular closet organizer: This highly ordered structure winds, loops and squishes the six feet of DNA that is your entire genome into its microscopic housing in every cell, known as nuclei.
If most of your nuclei are like a well-organized closet, sperm nuclei are more like a jam-packed storage unit. Unlike most cells, sperm don’t need to do anything with their DNA other than deliver it to the egg.
HP1E appears to help solve an unusual problem of sperm-meets-egg fertilization: That super-packed DNA has to be quickly unbundled and reformatted into the “normal” chromatin within mere minutes inside the egg before the embryo can begin to grow and divide in a process known as mitosis. How HP1E does this is still somewhat of a mystery, especially since the protein itself is not actually present during the unpacking step, but the discovery of a male protein involved in early embryo survival is somewhat surprising, the researchers said.
We sat down with two of the study authors, Drs. Harmit Malik and Mia Levine, to find out more about protein evolution, fruit fly sex and what their findings could mean for human fertility. Their answers have been edited for clarity and brevity.
Can you start by telling me how sperm’s packaging system is different from other cells’?
Malik: Traditional chromatin solves two problems: You need to package DNA or it would be too long to fit into the cell, but it also needs to do all the processes that a cell needs to carry out. As far as sperm are concerned, it’s all about one problem: Package it in as compact a form as possible. The normal chromatin proteins are not good enough for that solution, because sperm competition, or whether you’re going to outswim your brother sperm, is so intense, so sperm need to be incredibly small.
What happens to the sperm chromatin when it gets into the egg?
Malik: There’s a race that starts at fertilization. Mom and dad’s genomes have to be coordinated in the first division of the embryo, replicating and segregating together, but dad’s genome needs to get changed from its special chromatin into the traditional chromatin first. It’s almost like it’s changing its clothes in time to go to the party exactly with mom’s genome. And mom’s already ready, she’s going to go. There’s no checkpoint that asks her to wait until dad gets ready. So this is a very rapid dressing up, if you will.
Malik: Yeah, minutes, in fruit flies.
Levine: It’s a very rapid rate given the number of events that have to take place.
Malik: And if it doesn’t happen, as Mia showed in this study, dad’s genome is going to enter the egg, it’s going to be late, it’s not going to make it through mitosis, and the embryos are going to die.
How did you start working on this DNA quick-change?
Levine: Working on this particular problem was somewhat fortuitous. We are evolutionary biologists by training, and we are interested in one type of chromatin known as heterochromatin which evolves very rapidly. We wanted to study that evolution, so to do that we looked at a group of heterochromatin proteins called the “heterochromatin protein 1” gene family, or HP1.
One of those genes, which is called HP1E, looked really interesting to us. Some fruit fly species have actually lost this gene, as if it’s really not that important. When we went to look at what it does, it turned out that in the species of fruit fly that we study, Drosophila melanogaster, it was absolutely essential for male fertility. A heterochromatin protein which is important for male fertility — that’s somewhat unprecedented. And as we looked closer, in fact the sperm from flies missing this protein were abundant and motile. So you have a fertilized egg but the egg clearly isn’t developing. The life or death of the egg depends on dad’s genes, but not on the genes of the egg itself. That combined with the fact that this is a heterochromatin protein — we knew we were in new territory.
Malik: Can I interrupt with a tangent? When it comes to embryonic development, moms do most of the work — it’s true — and get most of the credit. Eggs have a lot more room and a lot more stuff than sperm do. And the traditional view, even a decade ago, is that sperm bring in dad’s genome and that’s it. The kind of mutation that Mia is talking about is beginning to highlight that dad’s bringing in more than just his genome. The dad needs to actually also seed some of the machinery that his genome will need to unravel in the proper way in the egg, which is like completely foreign territory. Whereas mom’s genome is living in the environment which is essentially replete with everything she needs.
Was it a surprise to find yourself studying sperm, as evolutionary biologists?
Levine: Well, we have a natural inclination to male fertility genes because they’re rapidly evolving. But studying sperm themselves was absolutely a surprise, because when you’re looking at a male fertility gene, if the males are sterile without that gene, generally you start at the end of sperm formation and find either no sperm or unhealthy sperm, and then you work your way back up the pathway. So it was a real surprise to see that males missing HP1E were unable to father any offspring and then look inside and find that they had normal sperm.
I was looking around online to find out whether fruit fly sperm look anything like human sperm and saw that some fruit flies have sperm that is two inches long. I did not know that!
Malik: Yes, it’s mostly tail, and the tail actually hangs around in the egg for quite a while after fertilization, and then it’s eventually excreted.
Wow, crazy. Do you have any favorite sperm jokes?
Levine: There are definitely all sorts of off-color comments made in the lab when you work on sperm and embryos. I don’t know who to attribute this to, but there’s a classic experiment for male sterility in fruit flies called a sperm depletion assay, where you take a male and give it a new virgin female every day to mate with, and you do this until the virgin female mated to the male no longer has any offspring, suggesting that you’ve completely depleted the male sperm supply. That’s often referred to as “the luckiest fly in the world” experiment.
So what happens to the embryos when HP1E is missing from sperm?
Malik: Dad’s genome can’t enter the first embryonic division. It basically gets [destroyed] when the embryo tries to divide. The correct term is “mitotic catastrophe.”
How do you think HP1E works?
Malik: What makes this protein unique is that it’s not inherited. It’s acting in some fashion we don’t understand on dad’s genome to prime it when the sperm are maturing. It’s fair to say we don’t know what it’s doing. We feel very confident about the fact that HP1E is leaving some kind of mark on the genome that’s inherited but HP1E itself is not inherited.
What does all this mean for human fertility?
Malik: HP1E is not the solution in other animals, but the problem is the same. We are confident that other animal species have come up with different solutions and it’s going to be very interesting to figure out what those solutions might be. In some cases it might be that mom has taken back control, but I feel like if that could happen it would have happened in fruit flies as well. So our hypothesis, which is totally just a working hypothesis, is that it could be other chromatin proteins that are uncharacterized for this function.
Levine: I think this study provides a map for honing in on those proteins, if they do exist — which we believe they do — in mammals.
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Rachel Tompa is a staff writer at Fred Hutchinson Cancer Research Center. She joined Fred Hutch in 2009 as an editor working with infectious disease researchers and has since written about topics ranging from nanotechnology to global health. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Reach her at firstname.lastname@example.org.
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