Lab Activities

Laboratory for Developmental Genetics

Research Activities

Haruhiko Koseki portrait

Team Director

Haruhiko Koseki

The majority of mammalian gene promoters are associated with specialized genomic regions called CpG islands (CGIs) that contribute to regulation of gene expression by attracting specific histone modifying enzymes. Recent studies have shown that CxxC domain-containing protein, KDM2B recognizes almost all CGIs and recruit a variant Polycomb (PcG) repressive complex1 (PCGF1-PRC1) to part of CGIs to induce mono-ubiquitination at lysine 119 of histone H2A (H2AK119ub1) mediated via RING1B, a RING-Finger protein. H2AK119ub1 further recruits PRC2/PRC1 complexes to repress transcription of PcG-target CGIs. PcG-target CGIs accounts for approximately 20% of CGIs, leaving the rest of CGIs free of PRC2/PRC1. The precise mechanisms by which PcG-target CGIs are established to specific CGIs remain poorly understood. In previous study, by using biochemical approach, we found that KDM2B associate with 26S proteasome upon treatment of mouse embryonic stem (ES) cells with MG132, a proteasome inhibitor. We also found that PCGF1-PRC1 exhibits poly-ubiquitination activity, which is canceled by introduction of catalytic-dead point mutations into RING1B (CPM) in mouse embryonic stem (ES) cells (Kondo, Ito et al 2025 Mol. Cell). To identify the poly-ubiquitination substrates of RING1B, we performed quantitative mass-spectrometry in CPM ES cells and found that BCOR, a component of PCGF1-PRC1 is increased at the protein level, suggesting that the protein level of BCOR is regulated via the catalytic activity of RING1B. Indeed, either the MG132-treatment or CPM induction leads to accumulation of BCOR at non-PcG-target CGIs, which also causes the increased binding of PRC2/PRC1 and consequently downregulates the associated CGI genes. Those results suggest that poly-ubiquitination activity of PCGF1-PRC1 and proteasome prevents non-PcG CGIs from PcG-mediated repression. Therefore, PCGF1-PRC1 and proteasome cooperatively ensure a proper CGI epigenome.

Schematic summary of poly-ubiquitination activity of PCGF1-PRC1 and proteasome shapes the epigenetic landscape of CpG islands

Laboratory for Developmental Genetics figure

Schematic summary of poly-ubiquitination activity of PCGF1-PRC1 and proteasome shapes the epigenetic landscape of CpG islands

Laboratory for Developmental Genetics figure

PCGF1–PRC1 contributes to the silencing of CGI-associated genes by bringing PRC2 to the PcG-target CGIs via H2AK119ub1. On the other hand, PCGF1–PRC1 also binds to non-PcG target CGIs to prevent to the excess binding of PcG proteins via poly-ubiquitination activity linked with proteasome. In catalytic-dead RING1B (CPM) cells, PcG proteins start to accumulate at the non-PcG target CGIs, which consequently downregulates the associated CGI genes.

PCGF1–PRC1 contributes to the silencing of CGI-associated genes by bringing PRC2 to the PcG-target CGIs via H2AK119ub1. On the other hand, PCGF1–PRC1 also binds to non-PcG target CGIs to prevent to the excess binding of PcG proteins via poly-ubiquitination activity linked with proteasome. In catalytic-dead RING1B (CPM) cells, PcG proteins start to accumulate at the non-PcG target CGIs, which consequently downregulates the associated CGI genes.

Recent Major Publications

  1. Iinuma T, Kurokawa T, Aoki T, Onodera A, Fukazawa T, Yamada D, Kitahara G, Okoshi M, Yamaguchi M, Okura H, Sasaki S, Sasako Y, Kira S, Sharif J, Tsuchiyama Y, Kobayashi M, Kobayashi N, Horikoshi T, Inaba Y, Hanaoka H, Okamoto Y, Hanazawa T, Koseki H, Motohashi S. Allogeneic iPSC-derived iNKT cells in recurrent head and neck cancer: a phase 1 trial. Nat Commun 16(1), 11666 (2025)

  2. Kondo T, Ito S, Takano J, Han Y, Endo T, Kondo K, Shibata M, Kawashima Y, Sugishita H, Harachi M, Sharif J, Seita J, Ohara O, Nakayama M, Koseki H. SKP1A bound to Polycomb-silenced genes mediates degradation of PRC2 and preconditions their activation. Mol Cell 85(17), 3306–3320.e6 (2025)

  3. Mei H, Hayashi R, Kozuka C, Kumon M, Koseki H, Inoue A. H2A.Z reinforces maternal H3K4me3 formation and is essential for meiotic progression in mouse oocytes. Nat Struct Mol Biol 32(10), 1883–1893 (2025)

  4. van Amerongen RA, Tuit S, Remst DF, Wouters AK, Siekman SL, Hagedoorn RS, van der Steen DM, Kester MG, de Ru AH, van der Horst G, Matsuda M, Ishikawa F, van Veelen PA, Falkenburg JH, Heemskerk MH. TCR-Based Therapy Directed against Kallikrein-Related Peptidase 4 Is Safe and Effective against Prostate Cancer. Cancer Immunol Res 13(8), 1145–1159 (2025)

  5. Harada M, Matsumoto T, Yamamoto M, Goda J, Idei A, Ohtaki K, Kojima N, Yoneda N, Miyauchi K, Katsura K, Ikeda M, Hanada K, Ishizuka-Katsura Y, Hosaka T, Hisano T, Kaizuka T, Yamamoto T, Matsuda M, Nakayama M, Sugimoto-Ishige A, Sakuma M, Hashimoto R, Takayama K, Nakayama M, Nguyen CT, Ishigaki H, Itoh Y, Hashizume Y, Yoshida M, Kawaguchi Y, Takeda M, Koseki H, Shirouzu M, Inoue J, Saito T. Monoclonal antibodies against human TMPRSS2 prevent infection by any SARS-CoV-2 variant. iScience 28(9), 113424 (2025)

  6. Fukushima-Nomura A, Kawasaki H, Yashiro K, Obata S, Tanese K, Ebihara T, Saeki H, Etoh T, Hasegawa T, Yazaki J, Seita J, Ohara O, Sekita A, Miyai T, Ashizaki K, Koseki H, Sakurada K, Kawakami E, Amagai M. An unbiased tissue transcriptome analysis identifies potential markers for skin phenotypes and therapeutic responses in atopic dermatitis. Nat Commun 16(1), 4981 (2025)

  7. Iyer S, Hattori N, Okuda H, Nakagawa T, Fujii S, Maeda T, Koseki H, Ito T. Usp21 Knockout Causes Abnormal Lipid Metabolism in Mouse and Its Polymorphism Correlates with Hypercholesterolemia in Outpatients. Int J Mol Sci 26(19), 9727 (2025)

  8. Kawamura YK, Ozonov EA, Papasaikas P, Kondo T, Nguyen NV, Stadler MB, Smallwood SA, Koseki H, Peters AH. Preventing CpG hypermethylation in oocytes safeguards mouse development. Dev Cell 60(23), 3285–3303.e9 (2025)

  9. Khalil J, Miyauchi K, Suzuki Y, Ki S, Harada Y, Sasaki T, Yamamoto Y, Hashimoto R, Yamamoto T, Matsuda M, Koseki H, Nakayama M, Fukasawa M, Wakita T, Ueno H, Noguchi K, Takayama K, Kubo M. The role of IL-4+ memory T cells in SARS-CoV-2 booster vaccination. Int Immunol, dxaf051 (2025)

  10. Koide R, Abe T, Harimoto T, Kamada  AJ, Saito Y, Guerrini  M, Fujii A, Parrish E, Horie  M, Kiyonari H, Yamamoto   K, Tomonaga K, Parrish  NF. Interferon and TLR genes, but not endogenous bornavirus-like elements, limit BoDV1 replication after intracerebral infection. PLoS Pathog, (2025)

  11. Newman AG, Sharif J, Bessa P, Zaqout S, Brown JP, Richter D, Dannenberg R, Nakayama M, Mueller S, Schaub T, Manickaraj S, Boehm-Sturm P, Ohara O, Koseki H, Singh PB, Tarabykin V. Glial reactivity and cognitive decline follow chronic heterochromatin loss in neurons. Nat Commun 16(1), 7325 (2025)

  12. Okazaki T, Nozaki K, Morimoto N, Otobe Y, Saito R, Abe S, Okajima M, Yoshitane H, Hatta T, Iemura S, Natsume T, Kosako H, Yamasaki M, Inoue S, Kondo T, Koseki H, Gotoh Y. Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense. Science 389(6755), 84–91 (2025)

  13. Ozaki K, Aoki T, Kobayashi M, Takami M, Kobayashi M, Ito T, Ogawa K, Tanaka H, Nishii K, Nishimura K, Motoyoshi K, Kojima I, Katsumi D, Shimizu D, Wang H, Kimura MY, Hirahara K, Koseki H, Higuchi Y, Motohashi S. Anti-tumor effect of intratumoral administration of induced pluripotent stem cell-derived NKT cells on glioblastoma through CD155/DNAM-1 interaction. Stem Cells Transl Med 14(9), szaf036 (2025)

  14. Sasa N, Kojima S, Koide R, Hasegawa T, Namkoong H, Hirota T, Watanabe R, Nakamura Y, Oguro-Igashira E, Ogawa K, Yata T, Sonehara K, Yamamoto K, Kishikawa T, Sakaue S, Edahiro R, Shirai Y, Maeda Y, Nii T, Chubachi S, Tanaka H, Yabukami H, Suzuki A, Nakajima K, Arase N, Okamoto T,... Ohshima S, Kinoshita M, Ito S, Arai T, Hirose M, Tanino Y, Nikaido T, Ichiwata T, Ohkouchi S, Hirano T, Takada T, Tazawa R, Morimoto K, Takaki M, Konno S, Suzuki M, Tomii K, Nakagawa A, ... Yamaguchi E, Ogawa S, Kanai T, Morita A, Matsuda F, Tamari M, Kumanogoh A, Tanaka Y, Ohmura K, Fukunaga K, Imoto S, Miyano S, Parrish NF, Okada Y. Blood DNA virome associates with autoimmune diseases and COVID-19. Nat Genet 57(1), 65–79 (2025)

Invited Presentations

  • Heaton SM. Using pooled cell libraries to associate genetic variance with responses to stimulus. Ko Group Meeting, Durham, Online, December 16–17 (2025)

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