Mitinori Saitou, M.D., Ph.D.Professor
The human body consists of a variety of cell types with distinct characters. An essential information code that defines a cell’s unique character is the epigenome, which refers to the whole-genome assembly of epigenetic modifications of chromatin. We are studying the mechanism of germ cell development, which, among all the cell types in the body, shows one of the most dynamic regulations of the epigenome to acquire totipotency, thereby aiming to understand the regulatory basis for many distinct cellular characters and to control them appropriately in vitro.
Research and EducationOur long-term goal is to understand the basis of epigenetic regulation and to appropriately control the growth, differentiation, and function of the cells in vitro. As a critical step toward this goal, we have been investigating signaling, global transcription, and epigenetic dynamics associated with germ cell development in mice. Based on the knowledge obtained, recently, using pluripotent stem cells [embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)], we have succeeded in precisely reconstituting the mouse germ-cell specification pathway in culture: ESCs/iPSCs are induced into epiblast-like cells (EpiLCs) and then into PGC-like cells (PGCLCs), which contribute to sperm and oocytes with full developmental potential. Based on this system, we have identified transcription factors sufficient for the induction of the germ-cell fate on EpiLCs, we have shown that a mesodermal factor, T, directly up-regulates the expression of germline determinants, and we have revealed quantitative dynamics of chromatin remodeling during in vitro PGC specification. To apply our findings to humans, we have initiated the analysis of early development/germ cell development of cynomolgus monkeys, a model for non-human primates. We have also initiated research on the induction of human germ cells from human iPSCs.
Fig.1: a, PGCs at embryonic day 7.25 (green: Blimp1-mVenus, red: TFAP2C), b, (top) transcription factor-induced PGCLCs (TF-PGCLCs) in EpiLC aggregates (green: Blimp1-mVenus, cyan: stella-ECFP), (bottom) EpiLC aggregates without TF induction, c, Spermatozoa derived from TF-PGCLCs, d, A model for epigenetic reprogramming during PGCLC induction, e, Zygotes of cynomolgus monkeys (left) and offspring obtained by reproductive technology of cynomolgus monkeys (right) (collaboration with Shiga University of Medical Science).
Fig.2: Members of the laboratory.
Recent Publications1.Kurimoto, K., Yabuta, Y., Hayashi, K., Ohta, H., Kiyonari, H., Mitani, T., Moritoki, Y., Kohri, K., Kimura, H., Yamamoto, T., Katou, Y., Shirahige, K., and Saitou, M. (2015). Quantitative dynamics of chromatin remodeling during germ cell specification from mouse embryonic stem cells, Cell Stem Cell, in press.
2.Nakamura, T., Yabuta, Y., Okamoto, I., Aramaki, S., Yokobayashi, S., Kurimoto, K., Sekiguchi, K., Nakagawa, M., Yamamoto, T., and Saitou, M. (2015). SC3-seq: A method for highly parallel and quantitative measurement of single-cell gene expression, Nucleic Acids Research, in press.
3.Aramaki, S., Hayashi, K., Kurimoto, K., Ohta, H., Yabuta, Y., Iwanari, H., Mochizuki, Y., Hamakubo, T., Kato, Y., Shirahige, K., and Saitou, M. (2013). A mesodermal factor, T, specifies mouse germ cell fate by directly activating germline determinants, Developmental Cell, 27, 516-529.
4.Nakaki, F., Hayashi, K., Ohta, H., Kurimoto, K., Yabuta, Y., and Saitou, M. (2013). Induction of the mouse germ cell fate by transcription factors in vitro. Nature, 501, 222-226.
5.Yamaji, M., Ueda, J., Hayashi, K., Ohta, H., Yabuta, Y., Kurimoto, K., Nakato, R., Shirahige, K., and Saitou, M. (2013). PRDM14 ensures naïve pluripotency through dual regulation of signaling and epigenetic pathways in mouse embryonic stem cells, Cell Stem Cell, 12, 368-382.
Anatomy and Cell BiologyProfessor: Mitinori Saitou
Associate Professor: Kazuki Kurimoto
Program-Specific Senior Lecturer: Ikuhiro Okamoto
Assistant Professor: Hiroshi Ohta, Fumio Nakaki
Program-Specific Assistant Professor: Sugako Ogushi, Yuichi Kumaki
Program-Specific Assistant Professor (CiRA): Shihori Yokobayashi
Program-Specific Assistant Professor (iCeMS): Yoji Kojima