Title:
EPINENETIC REGULATORS SUPPORTING TRASCRIPTION
Shigeaki Kato
Professor
Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo , Tokyo , Japan
Abstract:
Transcriptional controls by nuclear receptors have been recently shown to require chromatin reorganization and histone modifications. More recently, a number of epigenetic regulators supporting nuclear receptors have emerged, and histone modifying enzymes other than HATs/HDACs in multi-subunit complexes have been identified as transcriptional co-regulators. We are currently identifying epigenetic regulators/complexes by biochemical approaches(1-4), and a histone methyltransferase in response to extracellular glucose was biochemically identified.
Using a granulocytic differentiation system of HL60 cells induced by retinoic acid (RA) signaling through nuclear RA receptors (RARs), a histone lysine methyltransferase (HKMT), MLL5, was biochemically identified with O-linked N-acetylglucosamine transferase (OGT) as a multi-subunit complex and characterized as a novel ligand-dependent RAR co-activator. O-glycosylation was required for assembly and HKMT activity of the MLL5 complex. Nuclear O-glycosylation regulated promoter histone methylation during RA-induced granulocytic differentiation to define HL60 cell fate in RA-induced granulocytic differentiation(5). Currently, as one of histone modifications constituting histone code, histone O-glycosylation is under characterization (Fujiki et al., in revision). Thus, nuclear protein mono-glycosylation appears a vital protein modification for epigenetic controls.
References:
1. Takada, I. , Mihara, M., Suzawa, M., Ohtake, F., Kobayashi, S., Igarashi, M., Youn, M. Y., Takeyama, K., Nakamura, T., Mezaki, Y., Takezawa, S., Yogiashi, Y., Kitagawa, H., Yamada, G., Takada, S., Minami, Y., Shibuya, H., Matsumoto, K., Kato, S . : A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-g transactivation. Nat. Cell Biol . , 9, 1273-1285, 2007.
2. Yamagata , K., Fujiyama , S., Ito, S., Ueda, T., Murata, T., Naitou, M., Takeyama, K., Minami, Y., O’Malley, B. W., Kato, S. : Maturation of microRNA is hormonally regulated by a nuclear receptor.Mol. Cell , 36, 340-347, 2009.
3. Kim, M., Kondo, T., Takada, I. , Youn, M., Yamamoto, Y., Takahashi, S., Matsumoto, T., Fujiyama , S., Shirode, Y., Yamaoka, I. , Kitagawa H., Takeyama, K., Shibuya, H., Ohtake, F., Kato, S. : DNA demethylation in hormone-induced transcriptional derepression. Nature , 461, 1007-12, 2009.
4. Baba, A., Ohtake, F., Okuno, Y., Yokota, K., Okada, M., Imai, Y., Ni, M., Meyer, A. C., Igarashi, K., Kanno, J., Brown, M., Kato, S . : Signal-sensing activation of a histone lysine demethylase complex. Nat. Cell Biol . , in press.
5. Fujiki, R., Chikanishi, T., Hashiba, W., Ito, H., Takada, I. , Roeder, R. G., Kitagawa, H., Kato, S. : GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis. Nature , 459, 455-9, 2009.
