Crosstalk between transcriptional control and energy pathways, mediated by hub metabolites

Scientific Research on Innovative Areas, a MEXT Grant-in-Aid Project FY2011-2015

Fukamizu Group: Crosstalk regulation between the formation of the transcriptional environment and amino acid metabolism

Research Structure

Principal Investigator akiyoshi Akiyoshi Fukamizu
Life Science Center, Tsukuba Advanced Research Alliance
University of Tsukuba
Co-investigator takahasi-hidekazu-s05082-256x300 Hidekazu Takahashi
Associate Professor 
Yamaguchi University Graduate School of Medicine


Methylation of DNA and lysine and arginine residues is a major determinant of the formation of the transcriptional environment. The main methyl donor, S-adenosyl-L-methionine (SAM), is synthesized from methionine and ATP by SAM synthetase (SAMS) or methionine adenosyltransferase (MAT). This suggests a close linkage between the formation of the transcriptional environment and amino acid metabolism. However, little is known about the crosstalk regulation between these biological processes.
This project seeks to understand the fundamental importance of methyl transfer within the transcriptional environment. In order to unveil the biochemistry and genetics of basic biological functions, the interactions between methyl transfer and SAM metabolic pathways will be investigated in four types of nematode (C. elegans) SAMS mutants (sams-1, sams-3, sams-4 and sams-5). There are 116 methylase genes identified in nematodes to date, encoded in the genomes at a proportion of approximately 1% of all protein-coding genes. More specifically, our genetic and biochemical analyses will employ RNA interference knockout techniques to identify the methyltransferases directly involved in the e SAMS functions. In cooperation with our coinvestigator (H.T.), we will study the metabolic pathways of other amino acids than methionine in a mouse model, and explore the crosstalk regulation between these pathways and the formation of the transcriptional environment.

Recent Publications new

  1. Hashimoto, M., Murata, K., Ishida, J., Kanou, A., Kasuya, Y.,and *Fukamizu, A.
    Severe hypomyelination and developmental defects are caused in mice lacking protein arginine metyltransferase 1 (PRMT1) in the central nervous system.
    J. Biol. Chem.  291, 2237-2245(2016)pubmed
  2. Kim, JD., Park, KE., Ishida, J., Kako, K., Hamada, J., Kani, S., Takeuchi, M., Namiki, K., Fukui, H., Fukuhara, S., Hibi, M., Kobayashi, M., Kanaho, Y., Kasuya, Y., Mochizuki, N., and *Fukamizu, A.
    PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination.
    Sci Adv. 11, e1500615(2015)pubmed
  3. Hasegawa, M., Toma-Fukai, S., Kim, JD., Fukamizu, A., and *Shimizu, T.
    Protein arginine methyltransferase 7 has a novel homodimer-like structure formed by tandem repeats.  
    FEBS Lett. 588, 1942-1948 (2014)    pubmed
  4. Tamiya, H., Hirota, K., Takahashi, Y., Daitoku, H., Kaneko, Y., Sakuta, G., Iizaka, K., Watanabe, S., Ishii, N., and *Fukamizu, A. 
    Conserved SAMS function in regulating egg-laying in C. elegans 
    J. Recept. Signal Transduct. 33, 56-62 (2013)    pubmed
  5. TakahashiH .SunX., HamamotoM., YashirodaY., and *Yoshida, M. 
    The SAGA Histone Acetyltransferase Complex Regulates Leucine Uptake through the Agp3 Permease in Fission Yeast. 
    J. Biol. Chem. 287, 38158-38167 (2012)    pubmed
  6. Hashimoto, T., Perlot, T., Rehman, A., Trichereau, J., Ishiguro, H., Paolino, M., Sigl, V., Hanada, T., Hanada, R., Lipinski, S., Wild, B, Camargo, SM., Singer, D., Richter, A., Kuba, K., Fukamizu, A., Schreiber, S., Clevers, H., Verrey, F., *Rosenstiel, P., and *Penninger, JM.
    ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. 
    Nature. 487, 477-481 (2012)    pubmed
  7. Ozcan, L., Wong, CC., Li, G., Xu, T., Pajvani.,U., Park, SK., Wronska, A., Chen, BX., Marks, AR., Fukamizu, A., Backs, J., Singer, HA., Yates, JR 3rd., Accili, D., and *Tabas, I.
    Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. 
    Cell Metab. 15, 739-751 (2012)    pubmed
  8. Sakamaki, JI., Daitoku, H., Kaneko, Y., Hagiwara, A., Ueno, K., and *Fukamizu, A. 
    GSK3β regulates gluconeogenic gene expression through HNF4α and FOXO1. 
    J. Recept. Signal Transduct. 32, 96-101 (2012)    pubmed

Major Publications

  1. Takahashi, Y., Daitoku, H., Hirota, K., Tamiya, H., Yokoyama. A., Kako, K., Nagashima, Y., Nakamura, A., Watanabe, S., Yamagata, K., Yasuda, K., Ishii, N., and *Fukamizu, A. 
    Asymmetric arginine dimethylation determines lifespan in C. elegans by regulating forkhead transcription factor DAF-16.
    Cell Metab. 13, 505-516 (2011)
  2. Daitoku, H., Sakamaki, J-I., and *Fukamizu, A. 
    Regulation of FoxO transcription factors by acetylation and protein-protein interactions.
    Biochim. Biophys. Acta [review] in press (2011)
  3. Sakamaki, J-I., Daitoku, H., Ueno, K., Hagiwara, A., Yamagata, K., and *Fukamizu, A. 
    Arginine methylation of BAD counteracts its phosphorylation and inactivation by Akt.
    Proc. Natl. Acad. Sci. U.S.A. 108, 6085-6090 (2011)
  4. Yamagata, K., Daitoku, H., Takahashi, Y., Namiki, K., Hisatake, K., Kako, K., Mukai, H., Kasuya, Y., and *Fukamizu, A. 
    Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt.
    Mol. Cell
    32, 221-231 (2008)
  5. Hirota, K., Sakamaki, J-I., Ishida, J., Shimamoto, Y., Nishihara, S., Kodama, N., Ohta, K., Yamamoto, M., Tanimoto, K., and *Fukamizu, A. 
    A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding.
    J Biol Chem
    283, 32432-32441 (2008)
  6. Daitoku, H., and *Fukamizu, A.
    FOXO transcription factors in the regulatory networks of longevity.
    J. Biochem. 141, 769-774 [review] (2007)
  7. Takahashi, H., McCaffery, JM., Irizarry, RA., and *Boeke, JD.
    Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription.
    Mol. Cell 23, 207-217 (2006)
  8. Matsuzaki, H., Daitoku, H., Hatta, M., Aoyama, H., Yoshimochi, K., and *Fukamizu, A. 
    Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation.
    Proc. Natl. Acad. Sci. U.S.A. 102, 11278-11283 (2005)
  9. Daitoku, H., Hatta, M., Matsuzaki, H., Aratani, S., Ohshima, T., Miyagishi, M., Nakajima, T., and *Fukamizu, A. 
    Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.
    Proc. Natl. Acad. Sci. U.S.A. 101, 10042-10047 (2004)
  10. Ide, T., *Shimano, H., Yahagi, N., Matsuzaka, T., Nakakuki, M., Yamamoto, T., Nakagawa, Y., Takahashi, A., Suzuki, H., Sone, H., Toyoshima, H., Fukamizu, A., and Yamada, N.
    SREBPs suppress IRS-2-mediated insulin signalling in the liver.
    Nat. Cell Biol. 6, 351-357 (2004)

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