KATO Nuclear Complex


Research Director: Dr. Shigeaki Kato
(Professor, Institute of Molecular and Cellular Biosciences, The University of Tokyo)
Research Term: 2004-2009


Most people view the cell as a membrane within which many chemical reactions take place under the regulation of DNA from inside the nucleus. The cell takes in nutrients, undergoes reactions, ejects waste and reproduces. There is also the naive idea that each gene of DNA codes for some phenotype, a protein that has some function. In fact, though, one of the most interesting recent discoveries by cell biologists and biochemists is that everything is far more complicated than imagined. As one-celled bacterial organisms with naked DNA evolved to yeast and more complex multi-cellular organisms, the whole region of the DNA within the nucleus became far more involved, complex and interesting.

Shigeaki Kato has been interested in gene expression for over 20 years, particularly the involvement of nuclear receptors for binding steroid hormones, vitamins A and D and fat-soluble ligands. It appears that these kinds of molecules are necessary to switch the nuclear receptors, in order to activate gene expression. But there is more: the chromosome structure. As the state of the cell changes, it seems that the chromosome structure also changes, while influencing gene expression. Further, the chromosome structure is affected by a foam-like cloud of histone molecules. Thus, the picture of the cell nucleus that is emerging is: folded chromosomes made up of long chains of DNA surrounded by a dynamic system of histone, along with a large number of receptors and nuclear complexes of vastly different size, all interacting and affecting gene expression as well as cell differentiation.

Thus, there is talk about two types of codes: the historic genetic code, and a new code associated with the chromosomes and their related molecules and clusters of molecules. Kato believes that the key to understanding gene expression and cell differentiation is to understand chromosome regulation and its changes. The question now is what factors are responsible for modifying histone. Kato calls this the nuclear complex, and has already identified some of the components. However, a major problem is that these complexes come in various size and classes, which as of now are unknown. Some complexes have already been shown to have 1- to 15 subunits, with a total size of a huge molecular weight of 2 mega-Daltons. They seem to be localized, and complexes form and de-form depending on the space of the cell.

So far, Kato has employed several systems to isolate and purify the various sized nuclear complexes, and then to isolate and purify the component proteins. There is the density gradient technique, by which it is possible to separate the huge molecules and the single molecules by centrifugation. Also mass spectroscopy is employed. Using these techniques, a number of complexes associating with the nuclear receptor have already been identified. Still, new methods are needed.


Outline of Research

The major aim of the Kato Nuclear Complex project is to find and develop new means to isolate nuclear complexes and their components, while also observing as much structure as possible. These complexes might have a wide range of sizes, like those already identified, as well as huge ones with molecular weights of 10 and 20 mega Daltons. Unfortunately, these sizes fall between what is observable by electron microscopy (relatively large) and biochemical techniques (relatively small). Thus, completely new investigative techniques must be identified and developed, in consultation with experts from a variety of fields. But beyond their detection and analysis, the various functions of these complexes need to be identified. For this purpose knockout drosophila and mice are being used. Not just identification is needed, but a clear understanding of their scientific and biological impacts. The project is emphasizing the following research areas:

The most important part of the project is identification, since this is the beginning point. To do this, a wide variety of new technology is being sought for identification and structural clarification of a wide variety of complexes with vastly different sizes. Many fields of science and technology are being employed.

Once a number of complexes are identified, it is necessary to understand how signaling on the molecular level occurs between them as well as between various receptors in the nucleus. Then there is also the histone and the chromosome shape. It is postulated that these complexes and receptors interact with each other in a very dynamic, and perhaps unstable, way. Thus there is some type of associating factor that must be understood.

Drosophila are being used in order to identify the factors and functions. Emphasis is being placed on the eye of drosophila. Human genes are being introduced to evaluate the function. Another way is to knock out genes in mice so as to eliminate, for instance, one receptor. This might perhaps cause some problem in the brain. Using drosophila is very good since the genome has been completely sequenced and the life cycle is relatively short. Mutants can be made very quickly. Mice are also being used since they serve as a human analog. Thus, results from drosophila studies are guiding research in the much more slowly reproducing mice.


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