学術研究

研究の背景

我々の体はおよそ37兆の細胞から構成されていると言われていますが、もとは１つの細胞（受精卵）が胎盤の助けを借りつつ、その数を増やしながら（自己複製）、様々な臓器、組織、血液などを形つくっていきます（分化）。この過程では細胞がいつどこでどのような性質を獲得するかが正確にプログラムされています。一方、日常生活をおくる環境は細胞にとって決して安寧ではなく、細胞の内外に由来するいくつかのストレス性刺激は細胞、そして細胞核に含まれるDNAを傷つけてしまいます。DNA損傷の修復ミスや蓄積は細胞の過剰自己複製能獲得（がん化）や細胞周期の不可逆的停止（細胞老化）を引き起こす場合があります。また細胞老化はがん化を抑止する反応である一方で、老化細胞の蓄積は健康寿命に悪影響を及ぼします。したがって生命の誕生と恒常性維持は、細胞の振る舞い、すなわち状態を維持するのか、自身を増やすのか、分化するのか、老化するのかの選択に委ねられています。

研究の内容

私たちの研究室は、細胞の性質・機能が変移する過程、言い換えれば細胞の運命決定の仕組みに興味を持っています。ポリコーム群と呼ばれるクロマチン結合タンパク質は、細胞周期および分化に関わる遺伝子群の発現を調節し、その一方で、DNA修復反応にも寄与することで細胞の多能性、増殖、分化、そして老化に貢献しています（下図）。私たちは、ポリコーム群が細胞運命決定の中心因子として捉え、ポリコーム群による新しい細胞運命決定の分子機構を明らかにしていきます。研究手段として自家作製した遺伝子組換えマウスモデルを利用しますが、最終的には人の健康寿命改善に繋げたいと考えています。


発表論文

  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.
  
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