Yukihiro Yabuta

Establishment of a solid basis for informatic analysis on comparative epigenetic dynamics during germ cell development in humans, Cynomolgus monkeys and mice

Germ cells undergo extensive epigenetic reprogramming/programming during their development to differentiate into gametes that contributes to next generations. Investigations into epigenetic dynamics during germ cell development are critical not only for understanding basic mechanisms regarding how our genetic/epigenetic information are transmitted, but also for diseases arising from their abnormal regulations. It is also important to understand how germ cell development are conserved across species.

In 2011, we developed a method to induce mouse ES and iPS cells into primordial germ cell-like cells (PGCLCs), which had ability to produce healthy sperm and egg and normal offsprings. Since then, we have been developing to induce PGCLCs from human iPS cells, as well as Cynomolgus monkey ES and iPSCs. By using PGCLCs, we can apply many epigenetic analysis methods, such as ChIP-seq or bisulfite-seq.

Our study showed that, PGCLCs undergo genome-wide DNA demethylation in a similar manner as the in vivo germ cells in both mouse and human. In addition, specific transposable elements were resistant to demethylation in both species. However, the demethylation time scales were different between species that, mouse PGCLCs took less than 10 days to demethylate all genomic DNAs, whereas human PGCLCs required more than 120 days. This is in a reasonable range according to the gestation period of 20 days in mouse and 280 days in human, but the regulation mechanism and difference underlying DNA demethylation are still unknown. In ASHBi, we study on how DNA methylations are regulated during germ cell development and how those are conserved between species using human, mouse and Cynomolgus monkey PGCLCs.

Fig 1: Genome-wide demethylation occurs during oogonia induction from human iPS cells

Nagaoka SI, Nakaki F, Miyauchi H, Nosaka Y, Ohta H, Yabuta Y, Kurimoto K, Hayashi K, Nakamura T, Yamamoto T, Saitou M. ZGLP1 is a determinant for the oogenic fate in mice. Science. 2020 Mar 6;367(6482).

Sakai Y, Nakamura T, Okamoto I, Gyobu-Motani S, Ohta H, Yabuta Y, Tsukiyama T, Iwatani C, Tsuchiya H, Ema M, Morizane A, Takahashi J, Yamamoto T, Saitou M. Induction of the germ cell fate from pluripotent stem cells in cynomolgus monkeys. Biol Reprod. 2020 Mar 13;102(3):620-638.

Yamashiro C, Sasaki K, Yabuta Y, Kojima Y, Nakamura T, Okamoto I, Yokobayashi S, Murase Y, Ishikura Y, Shirane K, Sasaki H, Yamamoto T, Saitou M. Generation of human oogonia from induced pluripotent stem cells in vitro. Science. American Association for the Advancement of Science; 2018 Oct 19;362(6412):356–60.

Mitani T, Yabuta Y, Ohta H, Nakamura T, Yamashiro C, Yamamoto T, Saitou M, Kurimoto K. Principles for the regulation of multiple developmental pathways by a versatile transcriptional factor, BLIMP1. Nucleic Acids Res. 2017 Dec 1;45(21):12152–69.

Miyauchi H, Ohta H, Nagaoka S, Nakaki F, Sasaki K, Hayashi K, Yabuta Y, Nakamura T, Yamamoto T, Saitou M. Bone morphogenetic protein and retinoic acid synergistically specify female germ-cell fate in mice. EMBO J. EMBO Press; 2017 Nov 2;36(21):3100–19.

Kojima Y, Sasaki K, Yokobayashi S, Sakai Y, Nakamura T, Yabuta Y, Nakaki F, Nagaoka S, Woltjen K, Hotta A, Yamamoto T, Saitou M. Evolutionarily Distinctive Transcriptional and Signaling Programs Drive Human Germ Cell Lineage Specification from Pluripotent Stem Cells. Cell Stem Cell. 2017 Oct 5;21(4):517–532.e5.

Ohta H, Kurimoto K, Okamoto I, Nakamura T, Yabuta Y, Miyauchi H, Yamamoto T, Okuno Y, Hagiwara M, Shirane K, Sasaki H, Saitou M. In vitro expansion of mouse primordial germ cell-like cells recapitulates an epigenetic blank slate. EMBO J. EMBO Press; 2017 Jul 3;36(13):1888–907.

Nakamura T, Yabuta Y, Okamoto I, Sasaki K, Iwatani C, Tsuchiya H, Saitou M. Single-cell transcriptome of early embryos and cultured embryonic stem cells of cynomolgus monkeys. Sci Data. 2017 Jun 20;4:170067.

Yokobayashi S, Okita K, Nakagawa M, Nakamura T, Yabuta Y, Yamamoto T, Saitou M. Clonal variation of human induced pluripotent stem cells for induction into the germ cell fate. Biol Reprod. 2017 Jun 1;96(6):1154–66.

Honda A, Kawano Y, Izu H, Choijookhuu N, Honsho K, Nakamura T, Yabuta Y, Yamamoto T, Takashima Y, Hirose M, Sankai T, Hishikawa Y, Ogura A, Saitou M. Discrimination of Stem Cell Status after Subjecting Cynomolgus Monkey Pluripotent Stem Cells to Naïve Conversion. Sci Rep. 2017 Mar 28;7(1):487.

Research Group

Joined

Feb. 1, 2019