Epigenetics Drug Discovery Unit

Epigenetics is the research field that tackles information beyond genetic information, such as chemical, reversible and heritable modifications of genomic DNA and histones. We plan to develop the methods for production of a nucleosome, consisting of a DNA segment and core histones, with designed epigenetic modifications on it in order to reconstitute human epigenomic models of interest in vitro. Through the utilization of such an "epi-nucleosome" in high-throughput screening along with structure-based drug design approaches, we also plan to develop molecules that regulate lineage reprogramming of a cell and/or growth of a disease-related cell for rational development of novel "epi-drugs".

Research Fields

Biology & Biochemistry / Molecular Biology & Genetics / Clinical Medicine / Multidisciplinary

Research Subjects

• In vitro reconstitution of epigenetics and its application (Synthetic Biology)
• Understanding of molecular and regulatory mechanisms of epigenetics (Structural Biology)
• Development of regulators for epigenetic and/or genetic information (Drug Discovery)

Publications

1. *Niwa, H., *Handa, N., Tomabechi, Y., Honda, K., Toyama, M., Ohsawa, N., Shirouzu, M., Kagechika, H., Hirano, T., Umehara, T. and Yokoyama, S.:
   "Crystal structures of histone methyltransferase SET7/9 in complexes with adenosylmethionine derivatives"
   Acta Cryst. D69 in press (2013).
2. Hino, S., Sakamoto, A., Nagaoka, K., Anan, K., Wang, Y., Mimasu, S., Umehara, T., Yokoyama, S., Kosai, K.I. and Nakao, M.:
   "FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure"
   Nature Communications 3: 758. doi: 10.1038/ncomms1755 (2012).
3. #Umehara, T., Shirouzu, M. and #Yokoyama, S.:
   "Structural biology toward rational drug development in collaboration with molecular imaging"
   Curr. Med. Imaging Rev. 8, 308–313 (2012).
4. Wakamori, M., #Umehara, T. and #Yokoyama, S.:
   "A tandem insertion vector for large-scale preparation of nucleosomal DNA"
   Anal. Biochem. 423, 184–186 (2012).
5. Ito, T., Umehara, T., Sasaki, K., Nakamura, Y., Nishino, N., Terada, T., Shirouzu, M., Padmanabhan, P., Yokoyama, S., Ito, A. and Yoshida, M.:
   "Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors"
   Chemistry & Biology 18, 495–507 (2011).
6. *Sato, S., *Mimasu, S., *Sato, A., Hino, N., Sakamoto, K., Umehara, T. and Yokoyama, S.:
   "Crystallographic study of a site-specifically cross-linked protein complex with a genetically incorporated photo-reactive amino acid"
   Biochemistry 50, 250–257 (2011).
7. Mimasu, S., Umezawa, N., Sato, S., Higuchi, T., #Umehara, T. and #Yokoyama, S.:
   "Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1"
   Biochemistry 49, 6494–6503 (2010).
8. *Wakamori, M., *Umehara, T. and Yokoyama S.:
   "A series of bacterial co-expression vectors with rare-cutter recognition sequences"
   Protein Expr. Purif. 74, 88–98 (2010).
9. Umehara, T., Nakamura, Y., Wakamori, M., Ozato, K., Yokoyama, S. and Padmanabhan, B.:
   "Structural implications for K5/K12-di-acetylated histone H4 recognition by the second bromodomain of BRD2"
   FEBS Lett. 584, 3901–3908 (2010).
10. *Umehara, T., *Nakamura, Y., Jang, M.K., Nakano, K., Tanaka, A., Ozato, K., Padmanabhan, B. and Yokoyama, S.:
    "Structural basis for acetylated histone H4 recognition by the human BRD2 bromodomain"
    J. Biol. Chem. 285, 7610–7618 (2010).