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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

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  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.
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  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.
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  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.
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  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.
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  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.
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