DNA demethylation facilitates globin translation in myelodysplastic syndrome

• Project/Area Number: 24591397
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Hiroshima University
• Principal Investigator: MATSUI HIROTAKA 広島大学, 原爆放射線医科学研究所, 准教授 (60379849)
• Co-Investigator(Kenkyū-buntansha): KANAI Akinori 広島大学, 原爆放射線医科学研究所, 助教 (60549567)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: エピゲノム / DNAメチル化 / 骨髄異形成症候群 / 造血器腫瘍 / 次世代シーケンサー解析 / ヒストン修飾 / 次世代シーケンサー

Outline of Final Research Achievements

Abnormal epigenetic regulations have been shown to be involved in the pathogenesis and/or progression of myelodysplastic syndrome (MDS) and this characteristic of disease led to the introduction of DNA demethylating agents including Azacytidine and Aza-deoxycytidine (Aza-dC) for the clinical management of MDS. In this study, we characterized genes whose expressions are directly increased by Aza-dC using K562 cells, in which DNA demethylation induces hemoglobin (Hb) synthesis, as an experimental model. By analyzing changes in DNA methylation status and gene expression together with histone modification, we found that genes that are suppressed by promoter methylation but are ready to be transcribed will be activated by DNA demethylation. In addition, we elucidated a mechanism by which K562 cells produce Hb upon DNA demethylation.

Research Products

• [Journal Article] Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukemic transformation. (2014)
  • Author(s): Sashida, G., Harada, H., Matsui, H., Oshima, M., Yui, M., Harada, Y., Tanaka, S., Mochizuki-Kashio, M., Wang, C., Saraya, A., Muto, T., Hayasi, Y., Suzuki, K., Nakajima, H., Inaba, T., Koseki, H., Huang, G., Kitamura, T. and Iwama, A.
  • Journal Title: Nat. Commun. Volume: 5 Issue: 1 Pages: 5177-5177
  • DOI: 10.1038/ncomms5177
  • Peer Reviewed / Open Access
• [Journal Article] Novel functional small RNAs are selectively loaded onto mammalian Ago1 (2014)
  • Author(s): Yamakawa, N. Okuyama, K. Ogata, J. Kanai, A. Helwak, A. Takamatsu, M. Imadome, K. I. Takakura, K. Chanda, B. Kurosaki, N. Yamamoto, H. Ando, K. Matsui, H. Inaba, T. Kotani, A.
  • Journal Title: Nucleic Acids Res Volume: 未確定 Issue: 8 Pages: 5289-5301
  • DOI: 10.1093/nar/gku137
  • Peer Reviewed / Open Access
• [Journal Article] MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters (2014)
  • Author(s): Okuda H, Kawaguchi M, Kanai A, Matsui H, Kawamura T, Inaba T, Kitabayashi I, Yokoyama A
  • Journal Title: Nucleic Acid Research Volume: 未定 Issue: 7 Pages: 1-16
  • DOI: 10.1093/nar/gkt1394
  • NAID: 120005439160
  • Peer Reviewed
• [Journal Article] Ultradeep sequencing study of chronic hepatitis C virus genotype 1 infection in patients treated with daclatasvir, peginterferon, and ribavirin (2014)
  • Author(s): Murakami, E. Imamura, M. Hayes, C. N. Abe, H. Hiraga, N. Honda, Y. Ono, A. Kosaka, K. Kawaoka, T. Tsuge, M. Aikata, H. Takahashi, S. Miki, D. Ochi, H. Matsui, H. Kanai, A. Inaba, T. McPhee, F. Chayama, K.
  • Journal Title: Antimicrob Agents Chemother Volume: 58 Issue: 4 Pages: 2105-2112
  • DOI: 10.1128/aac.02068-13
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of sIL-2R levels in B-cell lymphomas (2013)
  • Author(s): Yoshida, N. Oda, M. Kuroda, Y. Katayama, Y. Okikawa, Y. Masunari, T. Fujiwara, M. Nishisaka, T. Sasaki, N. Sadahira, Y. Mihara, K. Asaoku, H. Matsui, H. Seto, M. Kimura, A. Arihiro, K. Sakai, A.
  • Journal Title: PloS one Volume: 8 Issue: 11 Pages: e78730-e78730
  • DOI: 10.1371/journal.pone.0078730
  • Peer Reviewed
• [Journal Article] Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice (2013)
  • Author(s): Shi, N. Hiraga, N. Imamura, M. Hayes, C. N. Zhang, Y. Kosaka, K. Okazaki, A. Murakami, E. Tsuge, M. Abe, H. Aikata, H. Takahashi, S. Ochi, H. Tateno-Mukaidani, C. Yoshizato, K. Matsui, H. Kanai, A. Inaba, T. McPhee, F. Gao, M. Chayama, K.
  • Journal Title: Gut Volume: 62 Issue: 7 Pages: 1055-1061
  • DOI: 10.1136/gutjnl-2012-302600
  • Peer Reviewed
• [Journal Article] Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. (2013)
  • Author(s): Nagamachi A
  • Journal Title: Cancer Cell Volume: 24 Issue: 3 Pages: 305-317
  • DOI: 10.1016/j.ccr.2013.08.011
  • Peer Reviewed
• [Journal Article] RUNX1/AML1 mutant collaborates with BMI1 overexpression in tnedevelopment of human and murine myelodysplastic syndromes. (2013)
  • Author(s): 原田結花、井上大地, 他
  • Journal Title: Blood Volume: 128(3) Issue: 17 Pages: 3434-3446
  • DOI: 10.1182/blood-2012-06-434423
  • Peer Reviewed
• [Presentation] DNAメチル化異常と造血器腫瘍 (2014)
  • Author(s): 松井啓隆
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31
  • Invited
• [Presentation] ポリADP-リボシル化による分裂期中心体の成熟を介した細胞分裂のマネージメント (2014)
  • Author(s): 松井啓隆, 稲葉俊哉
  • Organizer: 日本生化学会 第87回大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-16
• [Presentation] 大量データ解析を駆使した放射線影響解析手法の確立にむけて (2014)
  • Author(s): 松井啓隆, 河合秀彦, 金井昭教, 稲葉俊哉
  • Organizer: 日本放射線影響学会 第57回大会
  • Place of Presentation: 鹿児島
  • Year and Date: 2014-10-01
• [Presentation] Determination of 5-hydroxymethylcytosine at single base resolution using next generation sequencer (2014)
  • Author(s): Matsui H, Kanai A, Inaba T
  • Organizer: 第43回 国際実験血液学会(ISEH)年次集会
  • Place of Presentation: モントリオール(カナダ)
  • Year and Date: 2014-08-23
• [Presentation] Haploinsufficiency of Samd9L, encoding an endosome fusion facilitator, develops myeloid malignancies in mice mimicking human diseases with monosomy 7 (2014)
  • Author(s): 松井啓隆, 長町安希子, 尾崎佑子, 麻生博也, 本田浩章, 稲葉俊哉
  • Organizer: 第5回 日本血液学会国際シンポジウム
  • Place of Presentation: 浜松
  • Year and Date: 2014-05-24
• [Presentation] Determination of 5-hydroxymethylcytosine at single base resolution using next generation sequencer.
  • Author(s): Matsui H, Kanai A, Inaba T.
  • Organizer: 第75回 日本血液学会総会
  • Place of Presentation: 札幌
• [Presentation] Determination of 5-hydroxymethylcytosine at single base resolution using next generation sequencer.
  • Author(s): Matsui H, Kanai A, Inaba T.
  • Organizer: 第72回 日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] 造血器悪性腫瘍の発症・進展におけるエピゲノム異常の関与
  • Author(s): 松井啓隆, 金井昭教, 稲葉俊哉.
  • Organizer: 日本放射線影響学会 第56回大会
  • Place of Presentation: 青森
• [Presentation] Haploinsufficiency of Samd9L, encoding an endosome fusion facilitator, develops myeloid malignancies in mice mimicking human diseases with monosomy 7
  • Author(s): Matsui H, Nagamachi A, Ozaki Y, Asou H, Honda H, Inaba T.
  • Organizer: 2nd annual meeting of International Society of Experimental Hematology
  • Place of Presentation: ウィーン, オーストリア
• [Presentation] Haploinsufficiency of Samd9L, encoding an endosome fusion facilitator, develops myeloid malignancies in mice mimicking human diseases with monosomy 7
  • Author(s): Matsui H, Nagamachi A, Ozaki Y, Asou H, Honda H, Inaba T.
  • Organizer: 55th annual meeting of American Society of Hematology
  • Place of Presentation: ニューオーリンズ, 米国
• [Presentation] The translational machinery as a possible target of epigenetic therapy in MDS
  • Author(s): 松井啓隆
  • Organizer: 日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] The translational machinery as a possible target of epigenetic therapy in MDS
  • Author(s): 松井啓隆
  • Organizer: 日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] 次世代シーケンサーを用いた造血器悪性腫瘍のエピゲノム解析
  • Author(s): 松井啓隆
  • Organizer: 日本放射線影響学会大会
  • Place of Presentation: 仙台