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

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

Nakao Group: Molecular basis of metabolic reprogramming mediated by chromatin factors

Research Structure

Principal Investigator Mitsuyoshi Nakao Mitsuyoshi Nakao
Institute of Molecular Embryology and Genetics
Kumamoto University
Co-investigator Shinjiro Hino Shinjiro Hino
Assistant Professor
Institute of Molecular Embryology and Genetics
Kumamoto University





Epigenetic regulation of gene expression proceeds via short-term responses to internal and external stimuli, and via long-term responses that stem from the memories of the received stimuli. On the other hand, genes embedded in transcriptionally inactive chromatin can be unresponsive to stimuli. The mechanism of epigenetic gene regulation involves DNA methylation and chromatin formation, which play a crucial role in the maintenance — as well as collapse — of metabolic homeostasis. However, much remains to be clarified concerning the controlling mechanism underlying these processes.
The purpose of our research on epigenetic mechanism of metabolic homeostasis is to elucidate the role of flavin adenine dinucleotide (FAD)—dependent lysine-specific demethylase (LSD) 1 family members in the control of energy metabolism. Crosstalk regulation between the transcriptional environment and energy metabolism will be studied by focusing on LSD-1 and chromatin factors. More specifically, animal (mouse), cellular, and molecular models will be used to analyze metabolic regulation and chromatin remodeling related to lysine demethylation, the function of the hub metabolite FAD and the intracellular FAD biosynthesis pathway, and metabolic modulation and chromatin remodeling induced by DNA and lysine methylation. This study regarding the epigenetic control of cellular metabolism will be carried out in close cooperation with a coinvestigator (H.S.).

Recent Publications

  1. Nagaoka, K., *Hino, S., Sakamoto, A., Anan, K., Takase, R., Umehara, T., Yokoyama, S., Sasaki, Y., and *Nakao, M.
    Lysine-specific demethylase LSD2 suppresses lipid influx and metabolism in hepatic cells.
    Mol. Cell. Biol.  35,1068-1080(2015) pubmed
  2. Sakamoto, A., *Hino, S., Nagaoka, K., Anan, K., Takase, R., Matsumori, H., Ojima, H., Kanai, Y., Arita, K., and *Nakao, M.
    Lysine demethylase LSD1 coordinates glycolytic and mitochondrial metabolism in hepatocellular carcinoma cells.
    Cancer Res. 75,1445-1456(2015) pubmed
  3. *Hino, S., Nagaoka, and Nakao, M.
    Metabolism-epigenome crosstalk in physiology and diseases.
    J. Hum. Genet. 58, 410-415 (2013) pubmed
  4. *Hino, S., Sakamoto, A., Nagaoka, K., Anan, K., Wang, Y., Mimasu, S., Umehara, T., Yokoyama, S., Kosai, K., and *Nakao, M.
    FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. 
    Nature Commun. 3, Article number 758 (2012)    pubmed

Major Publications

  1. Sasai, N., Nakao, M., and *Defossez, PA.
    Sequence-specific recognition of methylated DNA by human zinc-finger proteins.
    Nucleic Acids Res. 38, 5015-5022 (2010)
  2. Mishiro, T., Ishihara, K., Hino, S., Tsutsumi, S., Aburatani, H., Shirahige, K., Kinoshita, Y., and *Nakao, M. 
    Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster.
    EMBO J. 28, 1234-1245 (2009)
  3. Watanabe, S., Ueda, Y., Akaboshi, S., Hino, Y., Sekita, Y., and *Nakao, M. 
    HMGA2 maintains oncogenic RAS-induced epithelial-mesenchymal transition in human pancreatic cancer cells.
    Am. J. Pathol. 174, 854-868 (2009)
  4. Wendt, KS., Yoshida, K., Itoh, T., Bando, M., Koch, B., Schirghuber, E., Tsutsumi, S., Nagae, G., Ishihara, K., Mishiro, T., Yahata, K., Imamoto, F., Aburatani, H., Nakao, M., Imamoto, N., Maeshima, K., *Shirahige, K., and *Peters, JM.
    Cohesin mediates transcriptional insulation by CCCTC-binding factor.
    Nature 451, 796-803 (2008)
  5. Sakamoto, Y., Watanabe, S., Ichimura, T., Kawasuji, M., Koseki, H., Baba, H., and *Nakao, M. 
    Overlapping roles of the methylated DNA binding protein MBD1 and polycomb group proteins in transcriptional repression of HoxA genes and heterochromatin foci formation.
    J. Biol. Chem. 282, 16391-16400 (2007)
  6. Ishihara, K., Oshimura, M., and *Nakao, M. 
    CTCF-dependent chromatin insulator is linked to epigenetic remodeling.
    Mol. Cell 23, 733-742 (2006)
  7. Watanabe, S., Ichimura, T., Fujita, N., Tsuruzoe, S., Ohki, I., Shirakawa, M., Kawasuji, M. and *Nakao, M. 
    Methylated DNA-binding domain 1 and methylpurine-DNA glycosylase links transcriptional repression and DNA repair in chromatin.
    Proc. Natl. Acad. Sci. U.S.A. 100, 12859-12864 (2003)
  8. Fujita, N., Watanabe, S., Ichimura, T., Ohkuma, Y., Chiba, T., Saya, H., and *Nakao, M. 
    MCAF mediates MBD1-dependent transcriptional repression.
    Mol. Cell. Biol. 23, 2834-2843 (2003)
  9. Ohki, I., Shimotake, N., Fujita, N., Jee, JG., Ikegami, T., Nakao, M., and *Shirakawa, M.
    Solution structure of the methyl-CpG-binding domain of human MBD1 in complex with a methylated DNA.
    Cell 105, 487-497 (2001)
  10. Kimura, Y., Koga, H., Araki, N., Mugita, N., Fujita, N., Takeshima, H., Nishi, T., Yamashima, T., Saido, TC., Yamasaki, T., Moritake, K., Saya, H., and *Nakao, M. 
    The involvement of calpain-dependent proteolysis of the tumor suppressor NF2 (merlin) in schwannomas and meningiomas.
    Nat. Med. 4, 915-922 (1998)

« PreviousNext »

« Back