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Knowledge Co-Creation - Profiles of researchers

At the forefront of epigenetics
Elucidating the mechanisms of gene expression and regulation

Hitoshi Kurumizaka
Professor, Faculty of Science and Engineering, Waseda University

Investigating the mechanisms of genetic programming

My expertise is in epigenetics, a new domain in the field of genetic research. The completion of the Human Genome Project meant that the human genome sequence is now fully determined. In terms of its functions, however, many remain to be investigated. In particular, our next challenge is to understand the developmental mechanism of a fertilized egg, or the cause and development of various diseases, in relation to the human genome. Epigenetics comes into play here: It is a study of mechanisms of gene expression and regulation, neither of which can be elucidated by genome sequences.

A human body is composed of about 60 trillion cells, but all of these cells originate from only one—a fertilized egg. The single cell keeps dividing and dividing to produce 60 trillion cells in the form of a human being. Importantly, all cells in an individual contain a single set of genetic information with no variations between the different parts of the body. Why, then, can a single cell grow into the hands, fingers, heart, eyes, skin, and all else just by a series of divisions? This so-called ‘development and differentiation’ is still one of the most fascinating mysteries in biology.

The general theory is that the secret lies in programming: In skin cells, for instance, the genes necessary to form the skin are turned on, while all the rest are turned off. In fact, it’s already been over 50 years since a cloning study demonstrated, using frog embryos, that it was possible to ‘reset’ such programming. This finding was further reinforced by the successful cloning of a sheep, a mammalian, and recently, Professor Shinya Yamanaka of Kyoto University succeeded in producing iPS cells (induced pluripotent stem cells) from human skin cells. iPS cells can transform into any type of organ, offering a novel approach to organ transplant therapy. When Professor Yamanaka won the Nobel Prize in Physiology or Medicine in 2012, the prize was jointly awarded to Professor John B. Gurdon who successfully performed frog cloning experiments. The prestigious prize was indeed the result of the tremendous contributions made by both researchers to the scientific field.

Despite such technological advancements, the exact programming mechanisms of turning genes on and off are yet to be clarified. I’ve spent quite a number of years working on this topic and only just recently started to understand, little by little, how genes are regulated. A human DNA molecule is about 2 meters in length, but it is folded tightly into the cell nucleus, which is merely 5 micrometers in diameter. And we know that gene transcription cannot take place when DNA is in a perfectly-folded state. In other words, DNA folding must open up at least partly to allow gene transcription. It is this folding and unfolding of DNA which has attracted attention as a possible means of controlling the on-off switching of genes.

Structural determination of the human centromere: The world’s first finding

Figure 1 The centromere, located at the center of the chromosome, is pulled from both sides by spindle fibers, enabling equipartition into two daughter cells.

Figure 2 Left, structure of the CENP-A nucleosome present in the centromere region; right, structure of the typical, H3 nucleosome.

Figure 3 A gene contains multiple nucleosomes joined together. A nucleosome consists of proteins wrapped around by two turns of DNA, presenting a disc-like structure.

One of my latest achievements is the structural determination of the human centromere, the central part of a chromosome (Figure 1). The constricted region of the centromere is considered to play a vital role in the transfer of genetic information during cell division. In 2011, our research team revealed that both ends of the DNA are open outward, in contrast to the remaining part of the DNA, which is tightly folded (Figure 2), and also that the nucleosome, the component of chromosomes, is structurally unique in the centromere region and contains an atypical protein. We used atomic-resolution imaging for this work for the first time in the world and published the above findings in the leading journal, Nature (→see reference).

The determination of the centromere structure is undoubtedly a great step forward towards understanding the mechanisms of not only gene expression but also chromosome abnormality-related diseases and the canceration of cells. Within an organism, cells exist in water and exhibit Brownian motion. It is ideal, therefore, to determine the dynamic structure in addition to the stationary structure. Concerning nucleosomes, they are joined together like beads on a string (Figure 3). In our study, we took out and analyzed only one of the nucleosomes and obtained its 3-D structure as shown in Figure 2.

We now hypothesize that the structure of nucleosomes is not uniform within a cell, with some possessing open ends while others show closed ends. Our next goal is to establish the dynamic structure of chromatin, a structure composed of multiple nucleosomes joined together. It is a great honor that our research project, ‘Chromatin structure, dynamics, and function,’ has been awarded a 2013 Grant-In-Aid for Scientific Research (under the Scientific Research on Innovative Areas) by the Ministry of Education, Culture, Sports, Science and Technology. As the principal investigator, I have been working hard on getting the five-year project into full swing.

My research interests also include the study of DNA repair mechanisms. DNA can be damaged by a range of factors. One example is a double-strand break caused by radiation; left unrepaired, the cell can become cancerous. Exposure to UV light induces another type of DNA damage by forming crosslinks between DNA bases; this too can develop into cancer. Although humans generally have physiological mechanisms to repair DNA damage, it may not be reparable in certain cases such as in those who congenitally lack the repair functions, or when the damage is too severe, leading to cancer development.

Other individuals may be susceptible to alcohol-related cancer. In our body, alcohol is metabolized to aldehyde followed by acetic acid. The formation of aldehyde is associated with drunken sickness and makes you feel nauseated. What aldehyde does is to cause interstrand DNA crosslinking which, if left unrepaired, prevents normal gene transcription and ultimately cell division. One form of alcohol-related cancer is Fanconi anemia, which has only recently started to be recognized in Japan. I have been conducting collaborative research project to uncover the mechanisms of DNA damage in Fanconi anemia.

Figure 4 From the original CG movie depicting the world of chromatin proposed by Prof. Kurumizaka.

Pursuing the dream of doing research

Professor Kurumizaka as a guitarist.

To be honest, I always wanted to be a professional musician since I was in primary school, and that was one of the reasons why I decided to go to a university in Tokyo (laughing). It was not until I went on to the graduate school that I finally began to realize that becoming a musician was probably beyond my abilities. (It certainly took long enough to sink in, right!) Fortunately, I met my mentor in research and started studying very hard. After that, doing research became increasingly interesting and eventually turned into my dream. Since I’ve always believed in pursuing a dream, I’m happy to be living the dream of doing research.

I also keep reminding my students not to give up on their dreams too easily when taking on jobs. Sadly, it is hard for MSc graduates to find research positions, and so they take many different career paths. Our PhD graduates, in contrast, managed to find their ways to various universities and private research institutes both inside and outside the country, and they are producing results. In fact, one of my PhD graduates has just been appointed an associate professor and launched his own lab. It’s my first time to see this happen, and this is genuinely rewarding. I now anticipate seeing more and more graduates with their own labs, and I dream about visiting them one after another in my life after retiring. The graduates would establish their own communication network to warn each other that I am headed their way, I will arrive soon and get in their way (laughing)—I’m looking forward to such a future.

Left: A scene in the lab (living space) (in TWIns; Building #50). Right: Summer camp (Karuizawa, 2013).

Hitoshi Kurumizaka
Professor, Faculty of Science and Engineering, Waseda University

Graduated from the School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, and qualified as a pharmacist in 1989; completed a PhD at the Graduate School of Science and Engineering, Saitama University in 1995.
1995 to 1997, postdoctoral fellow at the National Institute of Health (NIH), USA; 1997 to 2003, research fellow at RIKEN, Japan; 2003 to 2007, assistant professor at the Department of Electrical Engineering and Bioscience, Faculty of Science and Engineering, Waseda University; 2001 to 2007, visiting associate professor at the Department of Science of Biological Supramolecular Systems, Graduate School of Integrated Science, Yokohama City University; 2007 to 2008, associate professor at the Department of Electrical Engineering and Bioscience, Schools of Advanced Science and Engineering, Waseda University; 2008 to 2012, visiting professor at the Graduate School of Integrated Science, Yokohama City University; 2003 to present, visiting researcher at RIKEN; 2012 to present, visiting professor at the Graduate School of Medical Life Science, Yokohama City University; 2008 to present, professor at the Department of Electrical Engineering and Bioscience, Schools of Advanced Science and Engineering, Waseda University.