The Mystery Behind Transposons, Nature's Jumping Genes: Part 2

2022/07/06

In Part 1, we introduced the latest research of Professor Haruhiko Siomi and his colleagues, who have shown for the first time that eggs do not develop normally in golden hamsters that lack PIWI genes, which suppress transposon expression.

Part 2 begins with Prof. Siomi sharing the story of how transposons hold the key to maintaining species diversity.

Read Part 1 Here

While proliferated transposon expression may be associated with infertility, complete suppression of transposon activity during germ cell formation would prevent the creation of new mutations and halt biological evolution.

To preserve the potential for evolution, we also need a mechanism that produces new mutations at a particular frequency.

“According to Darwin's theory of evolution, an organism evolves through new mutations and their natural selection, and the lack of mutation would lead to no selection and, therefore, no survival. This is why I think our bodies are able to express transposons to some extent during the germ cell formation process and allow new mutations.”

Time and again, humans have been exposed to pandemics of infectious diseases such as COVID-19, but there are always survivors. This is precisely because of genome-level diversity, where infection-resistant genes are conserved at a certain frequency, even after an epidemic.

“That triggers the start of a new generation, and history repeats itself. In other words, transposons are the source of the mutations that we have within us. If we were to suppress them completely, that would mean zero mutations, and we would neither be able to evolve nor survive.

Genomic mutations are often single nucleotide units, but with transposons, large gene fragments can be jostled into place, creating massive changes. When newly transposed elements happen to be used as regulatory sequences, significant changes in gene expression can be expected. Of course, we cannot know whether all mutations will be good for us, but there will always be some among them that will allow us to cope with things like climate change, for example.”

“During the mammalian life cycle, reprogramming occurs twice. Reprogramming is the process through which the genome, having undergone various modifications, including histone modification and DNA methylation, is ‘stripped’ of all modifications.”

The first of these reprogrammings occurs in early embryos. The genome is stripped of modifications once around the time that the fertilized egg divides into two, four, and eight cells.

“From there, when the genome is 'cleared' and development begins, structural changes in the genome and modifications specific to that stage are promoted, which is how our bodies are ultimately formed. That is the first time, and the other reprogramming happens at the very beginning of germ cell formation when the genome is once again stripped bare. From there, DNA methylation and different histone modifications are gradually added in the process of forming sperm and eggs to create a structure specific to mature sperm and a chromatin structure specific to eggs.”

This is how our genome is twice laid bare. When this happens, transposons that have been suppressed by various mechanisms are strongly expressed.

“We call this a ‘transposon expression burst,’ which occurs twice during the mammalian life cycle. And until recently, people wondered why such a dangerous thing would happen. The thinking was that these transposon expression bursts could cause jumps to new locations, making a mess of the genome.”

To their surprise, however, researchers found that transposons didn’t jump very often following one of these bursts.

“When a burst takes place, transposons are expressed, but not much jumping occurs. As we tried to understand the mechanism that causes expression but not jumping, it became clear that, in the case of germ cells, this was due to the PIWI-piRNA pathway I mentioned earlier. However, this has yet to be explained in early embryos, which is what we are now working to understand.”

Prof. Siomi and his colleagues think they are getting close to an answer.

“In a few more years, we believe that we will be able to elucidate the mechanism that prevents transposons from jumping when they are expressed in bursts during the crucial early embryonic period.”

As he spearheads cutting-edge research, Prof. Siomi has also overseen all research at the Keio University School of Medicine as Vice Dean since October 2021.

“Today, I think labs need to be engaging the next generation and working on training more female researchers to close the gender gap. I believe that diversity is extremely important in creating new fields and new scientific breakthroughs, and I want to play my part in addressing these issues. We now have just three female professors in the School of Medicine. I’m sure it would be a strange sight for a researcher from the West to see a faculty meeting filled with men.

“Japan's population is now about 120 million, but it is expected to reduce to just half that in the next few decades. Yet many European countries with populations of 50–60 million are doing high-level science and maintaining strong economies. We still have a lot to learn from those countries, and I think diversity is part of that. At the Keio School of Medicine, we are mainly focused on how we can close the gender gap, and we have had some success. When people see the active role that women play here, I hope that it has a positive impact not only on the university but also on Japan as a whole.”

To create more opportunities for female researchers, Prof. Siomi believes that changes need to be made to encourage women to enter the natural sciences, starting in junior high as well as at the high school and university level.

“But this won’t work without changing parents’ minds. The first thing to do is to read books about things you are interested in, taking time for your own interests and hobbies. A lot of parents and guidance counselors might say that women wanting to go into the sciences should go into pharmacy, for example. But, to put it simply—don't believe what your parents or teachers tell you. If you choose a path based on what other people tell you, you will regret it after starting university. You’ll realize that it isn’t what you really want to do.”

Prof. Siomi says that it is important to continually think about what interests you in order to stay on the right path. When he realized that he wanted to do other kinds of research based on organic chemistry, which he majored in during his undergraduate and master's studies, he went back to graduate school to work in a laboratory conducting cancer research.

“I want to tell students to look at graduate programs first when deciding where to study. Entrance exams won’t necessarily guarantee admission to your university of choice. But if you want to pursue a career in research, you can look for a graduate school laboratory that is doing the research you are interested in and work to join that laboratory once you reach graduate school. Your search should be based on graduate laboratories that are doing what you are interested in, rather than on a university’s name or reputation.

“In my case, I had majored in organic chemistry at a university I chose after failing to get into my first pick. Although I studied hard and went on to earn a master's degree, I realized that I wanted to do other kinds of research in the future. At the time, I heard about a new laboratory in my field of interest that was recruiting people for a graduate school at Kyoto University, so I went to see if I could join. I hadn't studied medicine when I was an undergrad, but fortunately, the professor took a liking to me, and I was able to pass the entrance exam. At the lab, under the guidance of leading researchers including Nobel laureate Dr. Honjo. I was able to absorb a great deal of knowledge while studying the genetics of cancer.”

Ideally, students would all get into their university of choice. But even then, it doesn’t guarantee the ability to do the research they want to do. Therefore, you should spend your four years in university—or seven years if you start in high school—carefully searching for what you want to do. And in the end, Prof. Siomi stresses that it is best to go to a graduate school with laboratories that students find interesting, not their parents or teachers.

“One day, while working on my research at Kyoto University, a professor told me that an American researcher was coming to Japan and asked me to take him sightseeing in Kyoto. After a day of fumbling my way through conversations in English, the researcher invited me to come to his lab in the US, to which I had to say ‘yes.’ During my eight years abroad, I learned about a lot of things other than research. For example, I now try to stay in the lab as much as possible, which is what I did while I was in the US. The professor’s door is always open, and you’re welcome to step into their office anytime if you have something you want to talk about, whether it's to discuss science, ask for life advice, or anything else. Japanese people will often mind their manners and keep their thoughts to themselves, so I have tried to make my lab one where people can speak their minds as a 'lab without reservation.’”

Prof. Siomi wants his lab to be as friendly as possible, without the awkwardness of the old Japanese hierarchical senpai-kohai relationships. Everyone is on a first-name basis in his lab, and his students don’t have to worry about addressing him as ‘professor.’

Frank and open discussion requires people to speak up, and the free and open environment of Prof. Shimoi’s lab seems to prove that point, as it continues to stay on the cutting-edge of transposon research.

Haruhiko Siomi

Prof. Haruhiko Siomi received his master's degree from the Gifu University Graduate School of Agriculture in 1984 before entering a doctoral program at the Kyoto University Graduate School of Medicine. He completed his doctorate in 1988 and became a researcher at the Institute for Virus Research, Kyoto University. In 1990, he went to the University of Pennsylvania to serve as an HHMI fellow before becoming a postdoctoral fellow and assistant research professor in the Department of Biochemistry and Biophysics at the university’s School of Medicine. Starting in 1999, he served as a professor at the University of Tokushima's Institute for Genome Research and Graduate School of Medicine before assuming his current position in 2008. Since 2021, he has also served as Vice-President of Research at the Keio University School of Medicine.