Role of transcriptional co-repressor, TIF1b, in hematopoietic stem cell

• Project/Area Number: 21790906
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Chiba University
• Principal Investigator: MIYAGI Satoru Chiba University, 大学院・医学研究院, 助教 (20400997)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2009: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 造血幹細胞 / 自己複製 / 細胞分化 / クロマチン / 転写制御 / 核構造 / 遺伝子発現制御

Research Abstract

To assess the role of Tifb in the hematopoietic stem cells (HSCs), we disrupted the Tif1b gene specifically in hematopoietic cells. Tif1b^<F/F>-Tie2-Cre embryos died at mid-gestation due to anemia. In the mutant embryo, erythroblast maturation beyond the proerythroblast and survival of erythroblast were severely abrogated, indicating that Tif1b plays a critical role in embryonic erythropoiesis. Then, to elucidate the Tif1b function in HSC, we performed a series of transplantation assays and showed the cell-autonomous requirement for Tif1b in HSC repopulating capacity. Moreover, Tif1b^<F/F>-Tie2-Cre KSL cells proliferated and differentiated into myeloid cells poorly in vitro. To address the mechanism underlying the proliferation defect of Tif1b-deficient KSL cells, we conducted the microarray analysis and found that p21, but not p16, p19 and p57, was up-regulated in Kif1b-deficient KSL cells. Together, our findings suggest repression of p21 expression mediated by Tif1b is a critical for the maintenance of HSCs. On the other hand, we also observed that reduction and inappropriate localization of HP1a protein in the Kif1b-deficient KSL cells, so, TIF1b and HP1a may collaborate to repress the p21 expression.

Research Products

• [Journal Article] Direct activation of STAT5 by ETV6-LYN fusion protein promotes induction of myeloproliferative neoplasm with myelofibrosis. (2011)
  • Author(s): Takeda, Y., Nakaseko, C., Tanaka, H., Takeuchi, M., Yui, M., Saraya, A., Miyagi, S., Wang, C., Tanaka, S., Ohwada, C., Sakaida, E., Yamaguchi, N., Yokote, K., Hennighausen, L., Iwama A.
  • Journal Title: Br.J.Haematol. 153 Pages: 589-598
  • Peer Reviewed
• [Journal Article] Forced expression of the histone demethylase Fbxl10 maintains self-renewing hematopoietic stem cells (2011)
  • Author(s): Konuma, T., et al.
  • Journal Title: Experimental Hematology Volume: (In press)
  • Peer Reviewed
• [Journal Article] Direct activation of STAT5 by ETV6-Lyn fusion proteinpromotes induction of myeloproliferative neoplasm with myelofibrosis (2011)
  • Author(s): Takeda, Y., et al.
  • Journal Title: British Journal of Haematology Volume: (In press)
  • Peer Reviewed
• [Journal Article] The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells. (2010)
  • Author(s): Aoki, R., Chiba, T., Miyagi, S., Negishi, M., Konuma, T., Taniguchi, H., Ogawa, M., Yokosuka, O., Iwama, A.
  • Journal Title: J Hepatol. 52 Pages: 854-863
  • Peer Reviewed
• [Journal Article] The polycomb-group gene Bmil promotes hepatic stem cell expansion and tumorigenicity in both Ink4a/Arf-dependent and independent manners. (2010)
  • Author(s): Chiba T, Seki A, Aoki R, Ichikawa H, Negishi M, Miyagi S, Oguro H, Saraya A, Kamiya A, Nakauchi H, Yokosuka O, Iwama A.
  • Journal Title: Hepatology. 52 Pages: 1111-1123
  • Peer Reviewed
• [Journal Article] Identification of a novel TEL-Lyn fusion gene in primary myelofibrosis. (2010)
  • Author(s): Tanaka, H., Takeuchi, M., Takeda, Y., Sakai, S., Abe, D., Ohwada, C., Sakaida, E., Shimizu, N., Saito, Y., Miyagi, S., Iwama, A., Nakaseko, C.
  • Journal Title: Leukemia 24 Pages: 197-200
  • Peer Reviewed
• [Journal Article] Bmi1 promotes hepatic stem cell expansion and tumorigenicity in both Ink4a/Arf-dependent and -independent manners in mice. (2010)
  • Author(s): Chiba, T., et al.
  • Journal Title: Hepatology Volume: 52 Pages: 1111-1123
  • Peer Reviewed
• [Journal Article] The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells. (2010)
  • Author(s): Aoki, R., et al.
  • Journal Title: Journal of Hepatology Volume: 52 Pages: 854-863
  • Peer Reviewed
• [Journal Article] Identification of a novel TEL-Lyn fusion gene in primary mye lofibrosis (2010)
  • Author(s): Tanaka, H., et al.
  • Journal Title: Leukemia 24 Pages: 197-200
  • Peer Reviewed
• [Journal Article] Role of SoxB1 transcription factors in development. (2009)
  • Author(s): Miyagi, S., Kato, H., Okuda, A.
  • Journal Title: Cell Mol Life Sci. 66 Pages: 3675-3684
  • Peer Reviewed
• [Journal Article] Dmapl plays an essential role in the maintenance of genome integrity through the DNA repair process. (2009)
  • Author(s): Negishi, M., Chiba, T., Saraya, A., Miyagi, S., Iwama, A.
  • Journal Title: Genes Cells 14 Pages: 1347-1357
  • Peer Reviewed
• [Journal Article] Distinct expression of polycomb group proteins EZH2 and BMI1 in hepatocellular carcinoma. (2009)
  • Author(s): Yonemitsu, Y., Imazeki, F., Chiba, T., Fukai, K., Nagai, Y., Miyagi, S., Arai, M., Aoki, R., Miyazaki, M., Nakatani, Y., Iwama, A., Yokosuka, O.
  • Journal Title: Hum.Pathol. 40 Pages: 1304-1311
  • Peer Reviewed
• [Journal Article] Role of SoxB1 transcription factors in development (2009)
  • Author(s): Miyagi, S., et al.
  • Journal Title: Cellular and Molecular Lifescience 66 Pages: 3675-3684
  • Peer Reviewed
• [Journal Article] Dmapl plays an essential rolein the maintenance of genome in tegrity through the DNA repair process (2009)
  • Author(s): Negishi, M., et al.
  • Journal Title: Genes to Cells 14 Pages: 1347-1357
  • Peer Reviewed
• [Journal Article] Distinct expression of polycomb group proteins EZH2 and BMI1 in hepatocellular carcinoma (2009)
  • Author(s): Yonemitsu, Y., et al.
  • Journal Title: Human Pathology 40 Pages: 1304-1311
  • Peer Reviewed
• [Journal Article] Forced expression of the histone demethylase Fbxl10 maintains self-renewing hematopoietic stem cells.
  • Author(s): Konuma, T., Nakamura, S., Miyagi, S., Negishi, M., Chiba, T., Oguro, H., Yuan, J., Mochizuki-Kashio, M., Ichikawa, H., Miyoshi, H., Vidal, M., Iwama, A.
  • Journal Title: Exp.Hematol. in press
  • Peer Reviewed
• [Presentation] BRD1はHBO1、ING4とヒストンアセチル化酵素複合体を形成しヒストンH3のアセチル化に働く (2010)
  • Author(s): 宮城聡
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2010-09-24
• [Presentation] Brdl/Brpf2 is a core component of the Hbo1 HAT complex and regulates fetal liver erythropoiesis (2010)
  • Author(s): Satoru Miyagi
  • Organizer: The 1st JSH International Symposium
  • Place of Presentation: Akita University
  • Year and Date: 2010-07-16
• [Presentation] Brd1/Brpf2 is a core component of the Hbo1 HAT complex and regulates fetal liver erythropoiesis (2010)
  • Author(s): Satoru Miyagi
  • Organizer: The 1st JSH International Symposium
  • Place of Presentation: Akita University
  • Year and Date: 2010-07-16
• [Presentation] Brdl (Bromodomain-containing protein 1)-Hbol複合体による赤血球分化制御 (2009)
  • Author(s): 宮城聡
  • Organizer: 第71回日本血液学会学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2009-10-23
• [Presentation] Brd1(Bromodomain-containing protein 1)-Hbo1複合体による赤血球分化制御 (2009)
  • Author(s): 宮城聡
  • Organizer: 第71回日本血液学会学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2009-10-23
• [Presentation] 転写共役因子TIF1βは造血幹細胞の維持に働く (2009)
  • Author(s): 宮城聡
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2009-10-22
• [Presentation] 転写共役因子TIF1 β は造血幹細胞の維持に働く (2009)
  • Author(s): 宮城聡
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2009-10-22