Division of Developmental Regulation
Medical Cell Biology

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Projects

Our laboratory is studying the molecular basis of epigenetic cell regulation in development and human diseases with particular emphasis on cancer and developmental defects. Basically, variously differentiated somatic cells in our body have identical genome, but each of these cells has a distinct morphology and function, probably due to different use of gene information. The term epigenetic is defined as “heritable changes in gene expression that occur without a change in DNA sequence”. While information on DNA is transformed through RNA to protein, epigenetic regulation may include cytosine methylation, chromatin and nuclear structure, RNA synthesis and transport, and protein synthesis and post-translational modifications, and their turnover. These are involved in determining cell identity during development, regeneration, aging and cancer. To understand the essence of these phenomena, we perform medical science-oriented epigenetic researches, by studying how genes function through epigenetic regulatory network. Our current work is focused on 1) investigating the molecular mechanism of gene regulation by DNA methylation and methylated DNA binding proteins; 2) studying the role of chromatin proteins and regulatory RNAs in development and cancer; 3) identifying the molecules involving in chromatin insulators that have enhancer blocking and/or barrier activities; 4) studying nuclear structure, function and dynamics, including PML bodies and nuclear speckles; and 5) testing epigenetic regulatory molecules useful for medical diagnosis and therapy.

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Fig. 1.

 

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Fig. 2.

 

In various collaborations, the laboratory is active in structural biology of protein-protein and protein-DNA interactions. We determined the NMR structure of the complex of methyl-CpG dinucleotide and methylated DNA binding domain. Recent collaborative studies using Chip-on-Chip tilling array are identifying the sites of chromatin proteins on human and mammalian genomes. Many studies of epigenetic regulatory network are planned in association with development and cancer biology.

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Fig. 3.

 

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Fig. 4.

 

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Fig. 5.

 

Mechanism of Cell Regulation through Epigenetics

Epigenetic regulation is the mechanism by which gene function is selectively activated or inactivated in the cells. It provides higher-ordered and more specified genetic information, compared with the primary genome sequence itself. Recently, a variety of proteins including DNA methyltransferases, methylated DNA-binding proteins, histone-modifying enzymes, chromatin remodeling factors, and their multimolecular complexes have been identified and characterized. These findings facilitate our understanding of molecular details for wide variety of biological activities including development, regeneration, senescence and tumorigenesis. Studies on epigenetics will lead a new era for life science and become the major research area for emerging biological and medical discoveries. 

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Fig. 6.

 

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Fig. 7.

 

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Fig. 8.

 

Dynamics of Nuclear Structure and Function of Dynamic Nuclear Structure

It is considered that the nucleus is the origin of cellular function, because it can govern biological information within it. Transcription, RNA dynamics, DNA replication, DNA damage responses, and recombination can be regulated by accumulation of key molecules and their complexes at the respective unique domains in the nucleus. The nuclear domains are actively formed and dispersed in response to the cell environments. During the cell division, the nuclear architectures and domains are broken up and then re-established. Because many of the etiologies in cancer, autoimmune diseases and neurological disorders target the components of the nucleus, we investigate the dynamic structure and function of the nucleus, from the physiological and pathological aspects.

 

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Fig. 9.