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Academic Research

Academic interest

It is said that our body is composed of about 37 trillion cells but it is originally derived from one cell (fertilized egg). A fertilized egg grows while increasing the number of cells (self-renewal) and a group of defined cells forms various organs, tissues, or blood, etc. (differentiation). Such cell fate determination is precisely and spatio-temporally programmed during embryogenesis. On the other hand, the environment of daily life is not at all well-being for cells, and some stressful stimuli from inside and outside cells could damage the cells or genomes contained in the cell nucleus. Improper DNA repair or accumulation of DNA damages can cause cells to acquire excessive self-renewal capacity (cancer) and irreversible cell cycle arrest (cellular senescence). Cellular senescence is a self-defense response that inhibits cancer progression, while accumulating senescent cells has a negative impact on healthy life expectancy. Therefore, the birth and homeostasis of a life is left to the cell's behavior, that is, to maintain its state, to increase itself, to differentiate or to become senescent.

Our laboratory is interested in the process by which cells change their properties or functions, in other words, the mechanism of cell fate determination. Chromatin-binding proteins, called Polycomb-group, regulate the expression of genes involved in cell cycle and differentiation and also contribute to DNA repair reactions, thereby playing central roles in cell pluripotency, proliferation, differentiation, and senescence (shown below). By studying the functions of Polycomb-group we would like to clarify the molecular mechanism of cell-fate decision making. Ultimately, we hope to improve human healthy life expectancy. As a main research tool, we are using a genetically modified mouse model created in-house.

Research paper

  1. Kato T, Yamamoto M, Honda Y, Orimo T, Sasaki I, Murakami K, Hemmi H, Fukuda-Ohta Y, Isono K, Takayama S, Nakamura H, Otsuki Y, Miyamoto T, Takita J, Yasumi T, Nishikomori R, Matsubayashi T, Izawa K, Kaisho T. (2021) Augmentation of STING-induced type I interferon production in COPA syndrome. Arthritis Rheumatol., doi: 10.1002/art.41790
  2. Kajioka D, Suzuki K, Matsushita S, Hino S, Sato T, Takada S, Isono K, Takeo T, Kajimoto M, Nakagata N, Nakao M, Suyama M, DeFalco T, Miyagawa S, Yamada G. (2021) Sexual fate of murine external genitalia development: Conserved transcriptional competency for male-biased genes in both sexes. Proc. Natl. Acad. Sci. USA., 118, e2024067118, doi.org/10.1073/pnas.2024067118.
  3. Bae J, Choi SP, Isono K, Lee JY, Park SW, Choi CY, Han J, Kim SH, Lee HH, Park K, Jin HY, Lee SJ, Park CG, Koseki H, Lee YS, Chun T. (2019) Phc2 controls hematopoietic stem and progenitor cell mobilization from bone marrow by repressing Vcam1 expression. Nat Commun, doi: 10.1038/s41467-019-11386-4.
  4. Dong Y, Isono KI, Ohbo K, Endo TA, Ohara O, Maekawa M, Toyama Y, Ito C, Toshimori K, Helin K, Ogonuki N, Inoue K, Ogura A, Yamagata K, Kitabayashi I, Koseki H. (2017) EPC1/TIP60-mediated histone acetylation facilitates spermiogenesis in mice. Mol Cell Biol, doi:10.1128/MCB.00082-17.
  5. Torrente L, Sanchez C, Moreno R, Chowdhry S, Cabello P, Isono K, Koseki H, Honda T, Hayes JD, Dinkova-Kostova AT, de la Vega L. (2017) Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses. Oncogene, doi:10.1038/onc.2017.221.
  6. Ikawa T, Masuda K, Endo TA, Endo M, Isono K, Koseki Y, Nakagawa R, Kometani K, Takano J, Agata Y, Katsura Y, Kurosaki T, Vidal M, Koseki H, Kawamoto H. (2016) Conversion of T cells to B cells by inactivation of polycomb-mediated epigenetic suppression of the B-lineage program. Genes Dev 30, 2475-2485.
  7. Inoue T, Morita M, Hijikata A, Fukuda-Yuzawa Y, Adachi S, Isono K, Ikawa T, Kawamoto H, Koseki H, Natsume T, Fukao T, Ohara O, Yamamoto T, Kurosaki T. (2015) CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability. J Exp Med 212, 1465-1479.
  8. Dewi V, Kwok A, Lee S, Lee MM, Tan YM, Nicholas HR, Isono KI, Weinert B, Mak KS, Knights AJ, Quinlan KG, Cordwell SJ, Funnell AP, Pearson RC, Crossley M. (2015) Phosphorylation of Kruppel-like Factor 3 (KLF3/BKLF) and C-terminal Binding Protein 2 (CtBP2) by Homeodomain Interacting Protein Kinase 2 (HIPK2) Modulates KLF3 DNA Binding and Activity. J Biol Chem 290, 8591-8605
  9. Visconte V, Tabarroki A, Zhang L, Parker Y, Hasrouni E, Mahfouz R, Isono K, Koseki H, Sekeres MA, Saunthararajah Y, Barnard J, Lindner D, Rogers HJ, Tiu RV. (2014) Splicing factor 3b subunit 1 (Sf3b1) haploinsufficient mice display features of low risk Myelodysplastic syndromes with ring sideroblasts. J Hematol Oncol 7, doi:10.1186/s13045-014-0089-x.
  10. Koike H, Ouchi R, Ueno Y, Nakata S, Obana Y, Sekine K, Zheng YW, Takebe T, Isono K, Koseki H, Taniguchi H. (2014) Polycomb group protein ezh2 regulates hepatic progenitor cell proliferation and differentiation in murine embryonic liver. PLoS One 9, e104776, doi: 10.1371/journal.pone.0104776.
  11. Koike H, Ueno Y, Naito T, Shiina T, Nakata S, Ouchi R, Obana Y, Sekine K, Zheng YW, Takebe T, Isono K, Koseki H, Taniguchi H. (2014) Ring1B promotes hepatic stem/progenitor cell expansion through simultaneous suppression of Cdkn1a and Cdkn2a in mice. Hepatology 60, 323-333.
  12. Wang C, Sashida G, Saraya A, Ishiga R, Koide S, Oshima M, Isono K, Koseki H, Iwama A. (2014) Depletion of Sf3b1 impairs proliferative capacity of hematopoietic stem cells but is not sufficient to induce myelodysplasia. Blood 123, 3336-3343.
  13. Matsunawa M, Yamamoto R, Sanada M, Sato-Otsubo A, Shiozawa Y, Otsu M, Isono K, Hoseki H., Nakauchi H, Ogawa S. (2014) Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia. Leukemia 28, 1844-1850.
  14. Kondo T, Isono K, Kondo K, Endo TA, Itohara S, Vidal M, Koseki H. (2014) Polycomb potentiates Meis2 activation in midbrain by mediating interaction of the promoter with a tissue-specific enhancer. Dev Cell 28, 94-101.
  15. #Isono K, Endo AT, Ku M, Yamada D, Suzuki R, Sharif J, Ishikura T, Toyoda T, Bernstein BE, #Koseki H. (2013) SAM domain polymerization links subnuclear clustering of PRC1 to gene silencing. Dev Cell 26, 565-577. (#co-correspoding) *Featured in Preview: Sievers C and Paro R. (2013) Polycomb group protein bodybuilding: Working out the routines. Dev Cell 26, 556-558.
  16. Choi DW, Na W, Kabir MH, Yi E, Kwon S, Yeom J, Ahn JW, Choi HH, Lee Y, Seo KW, Shin MK, Park SH, Yoo HY, Isono K, Koseki H, Kim ST, Lee C, Kwon YK, Choi CY. (2013) WIP1, a Homeostatic Regulator of the DNA Damage Response, Is Targeted by HIPK2 for Phosphorylation and Degradation. Mol Cell. 51, 374-385.
  17. Visconte V, Rogers HJ, Singh J, Barnard J, Bupathi M, Traina F, McMahon J, Makishima H, Szpurka H, Jankowska A, Jerez A, Sekeres MA, Saunthararajah Y, Advani AS, Copelan E, Koseki H, Isono K, Padgett RA, Osman S, Koide K, O'Keefe C, Maciejewski JP, Tiu RV. (2012) SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes. Blood 120, 3173-3186.
  18. Endoh M, Endo TA, Endoh T, Isono K, Sharif J, Ohara O, Tetsuro T, Ito T, Eskeland R, Bickmore WA, Vidal M, Bernstein BE, Koseki H. (2012) Histone H2A mono-ubiquitination is a crucial step to mediate PRC1-dependent repression of developmental genes to maintain ES cell identity. PLoS Genet. 8: e1002774. doi:10.1371/journal.pgen.1002774.
  19. Li X, Isono K, Yamada D, Endo TA, Endoh M, Shinga J, Mizutani-Koseki Y, Otte AP, Casanova M, Kitamura H, Kamijo T, Sharif J, Ohara O, Toyada T, Bernstein BE, Brockdorff N, Koseki H. (2011) Mammalian polycomb-like Pcl2/Mtf2 is a novel regulatory component of PRC2 that can differentially modulate polycomb activity both at the Hox gene cluster and at Cdkn2a genes. Mol Cell Biol. 31, 351-364.
  20. Inoue T, Kagawa T, Inoue-Mochita M, Isono K, Ohtsu N, Nobuhisa I, Fukushima M, Tanihara H, Taga T. (2010) Involvement of the Hipk family in regulation of eyeball size, lens formation and retinal morphogenesis. FEBS Lett. 16, 3233-3238.
  21. Tanuma N, Kim SE, Beullens M, Tsubaki Y, Mitsuhashi S, Nomura M, Kawamura T, Isono K, Koseki H, Sato M, Bollen M, Kikuchi K, Shima H. (2008) Nuclear inhibitor of protein phosphatase-1 (NIPP1) directs protein phosphatase-1 (PP1) to dephosphorylate the U2 snRNP component, spliceosome-associated protein 155 (Sap155). J. Biol. Chem. 283, 35805-35814.
  22. Puschendorf M, Terranova R, Boutsma E, Mao X, Isono KI, Brykczynska U, Kolb C, Otte AP, Koseki H, Orkin SH, van Lohuizen M, Peters AH. (2008) PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos. Nat. Genet. 40, 411-420.
  23. Hiraoka S, Furuichi T, Nishimura G, Shibata S, Yanagishita M, Rimoin DL, Superti-Furga A, Nikkels PG, Ogawa M, Katsuyama K, Toyoda H, Kinoshita-Toyoda A, Ishida N, Isono K, Sanai Y, Cohn DH, Koseki H, Ikegawa S. (2007) Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human. Nat. Med. 13, 1363-1367.
  24. Miyake Y, Kaise H, Isono K, Koseki H, Kohno K, Tanaka M. (2007) Protective role of macrophages in noninflammatory lung injury caused by selective ablation of alveolar epithelial type II Cells. J. Immunol. 178, 5001-5009.
  25. Uchida H, Iwano M, Isono K, Kuroiwa T, Ohyama K, Tomizawa K. (2007) Increasing the copy number of rbcL genes in Chlamydomonas reinhardtii chloroplast genome affects neither cell proliferation nor distribution of pyrenoid antigens to Rubisco holoenzyme antibody. Cytologia, 72, 209-211.
  26. de la Cruz CC, Kirmizis A, Simon MD, Isono K, Koseki H, Panning B. (2007) The Polycomb Group Protein SUZ12 regulates histone H3 lysine 9 methylation and HP1alpha distribution. Chromosome Res. 15, 299-314.
  27. Takada Y, Isono K, Shinga J, Turner JM, Kitamura H, Ohara O, Watanabe G, Singh PB, Kamijo T, Jenuwein T, Burgoyne PS, Koseki H. (2007) Mammalian Polycomb Scmh1 mediates exclusion of Polycomb complexes from the XY body in the pachytene spermatocytes. Development 134, 579-590.
  28. Sato T, Endoh M, Yoshida H, Yasuo S, Katsuno T, Saito Y, Isono K, Koseki H. (2006) Mammalian Polycomb complexes are required for Peyer's patch development by regulating lymphoid cell proliferation. Gene 379, 166-174.
  29. Aikawa Y, Nguyen LA, Isono K, Takakura N, Tagata Y, Schmitz ML, Koseki H, Kitabayashi I. (2006) Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation. EMBO J. 25, 3955-3965.
  30. #Fujimura Y, #Isono K, Vidal M, Endoh M, Kajita H, Mizutani-Koseki Y, Takihara Y, van Lohuizen M, Otte A, Jenuwein T, Deschamps J, Koseki H. (2006) Distinct roles of Polycomb group gene products in transcriptionally repressed and active domains of Hoxb8. Development 133, 2371-2381. (#equal contributed)
  31. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP, Melton DA, Gifford DK, Jaenisch R, Young RA. (2006) Control of developmental regulators by polycomb in human embryonic stem cells. Cell 125, 301-313.
  32. Isono K, Nemoto K, Li Y, Takada Y, Suzuki R, Katsuki M, Nakagawara A, Koseki H. (2006) Overlapping roles for homeodomain-interacting protein kinases Hipk1 and Hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals. Mol. Cell. Biol. 26, 2758-2771.
  33. Uchida H, Isono K, Tomizawa K, Iwano M, Yamashita H, Fukuzawa H, Ohyama K, Yokota A. (2005) Synthesis of Rubisco gene products is upregulated by increasing the copy number of rbcL gene in Chlamydomonas chloroplast genome, without increased accumulation of the two Rubisco subunits. Plant Biotechnol., 22, 145-149
  34. Isono K, Fujimura Y, Shinga J, Yamaki M, O-Wang J, Takihara Y, Murahashi Y, Takada Y, Mizutani-Koseki Y, Koseki H. (2005) Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression of Hox genes. Mol. Cell. Biol. 25, 6694-6706.
  35. Baba T, Shimizu T, Suzuki Y, Ogawara M, Isono K, Koseki H, Kurosawa H, Shirasawa T. (2005) Estrogen, insulin, and dietary signals cooperatively regulate longevity signals to enhance resistance to oxidative stress in mice. J. Biol. Chem., 280, 16417-16426.
  36. Isono K, Mizutani-Koseki Y, Komori T, Schmidt-Zachmann MS, Koseki H. (2005) Mammalian polycomb-mediated repression of Hox genes requires the essential spliceosomal protein Sf3b1. Genes Dev., 19, 536-541.
  37. Kaneko T, Miyagishima H, Hasegawa T, Mizutani-Koseki Y, Isono K, Koseki H. (2003) The mouse YAF2 gene generates two distinct transcripts and is expressed in pre-and postimplantation embryos. Gene, 315, 183-192.
  38. Miyagishima H, Isono K, Fujimura Y, Iyo M, Takihara Y, Masumoto H, Vidal M, Koseki H. (2003) Dissociation of mammalian Polycomb-group proteins, Ring1B and Rae28/Ph1, from the chromatin correlates with configuration changes of the chromatin in mitotic and meiotic prophase. Histochem. Cell Biol., 120, 111-119.
  39. Horie A, Isono K, Koseki H. (2003) Generation of a monoclonal antibody against the mouse Sf3b1 (SAP155) gene product for U2 snRNP component of spliceosome. Hybrid. Hybridomics, 22, 117-119.
  40. Ikegami T, Suzuki Y, Shimizu T, Isono K, Koseki H, Shirasawa T. (2002) Model mice for tissue-specific deletion of the manganese superoxide dismutase (MnSOD) gene. Biochem. Biophys. Res. Commun., 296, 729-736.
  41. Suzuki M, Mizutani-Koseki Y, Fujimura YI, Miyagishima H, Kaneko T, Takada Y, Akasaka T, Tanzawa H, Takihara Y, Nakano M, Masumoto H, Vidal M, Isono K, Koseki H. (2002) Involvement of the Polycomb-group gene Ring1B in the specification of the anterior-posterior axis in mice. Development, 129, 4171-4183.
  42. Yamaki M, Isono K, Takada Y, Abe K, Akasaka T, Tanzawa H, Koseki H. (2002) The mouse Edr2 (Mph2) gene has two forms of mRNA encoding 90- and 36-kDa polypeptides. Gene, 288, 103-110.
  43. Yoshimoto K, Sakaiya M, Isono K, Kobayashi H. (2001) Comparison of strength of endogenous and exogenous gene promoters in Arabidopsis chloroplasts. Plant Biotech., 18, 135-142.
  44. Nakai D, Yuasa S, Takahashi M, Shimizu T, Asaumi S, Isono K, Takao T, Suzuki Y, Kuroyanagi H, Hirokawa K, Koseki H, Shirasawa T. (2001) Mouse homologue of coq7/clk-1, longevity gene in Caenorhabditis elegans, is essential for coenzyme Q synthesis, maintenance of mitochondrial integrity, and neurogenesis. Biochem. Biophys. Res. Commun., 289, 463-471.
  45. Isono K, Abe K, Tomaru Y, Okazaki Y, Hayashizaki Y, Koseki H (2001) Molecular cloning, genetic mapping, and expression of the mouse Sf3b1 (SAP155) gene for U2 snRNP component of spliceosome. Mam. Genome, 12, 192-198.
  46. Isono K, Satoh K, Kobayashi K (2000) Molecular cloning of a cDNA encoding a novel Ca(2+)-dependent nuclease of Arabidopsis that is similar to staphylococcal nuclease. Biochim. Biophys. Acta., 1491, 267-272.
  47. Isono K, Yamamoto H, Satoh K, Kobayashi H (1999) An Arabidopsis cDNA encoding a DNA-binding protein that is highly similar to the DEAH family of RNA/DNA helicase genes. Nucleic Acids Res., 27, 3728-3735.
  48. Isono K, Shimizu M, Yoshimoto K, Niwa Y, Satoh K, Yokota A, Kobayashi H (1997) Leaf-specifically expressed genes for polypeptides destined for chloroplasts with dominants of 70 factors of bacterial RNA polymerases in Arabidopsis thaliana. Proc. Natl. Acad. Sci. USA., 94, 14948-14953.
  49. Isono K, Niwa Y, Satoh K, Kobayashi H (1997) Evidence for transcriptional regulation of plastid genes in Arabidopsis thaliana roots. Plant Physiol., 114, 623-630.