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A role of Bcl6 in induction of somatic hypermutation in immunoglobulin gene

Research Project

Project/Area Number 16390140
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionChiba University

Principal Investigator

TAKESHI Tokuhisa  Chiba University, Graduate School of Medicine, Professor, 大学院・医学研究院, 教授 (20134364)

Co-Investigator(Kenkyū-buntansha) HATANO Masahiko  Chiba University, Gene Research Center, Associate Prof., バイオメディカル研究センター, 助教授 (20208523)
ARIMA Masafumi  Chiba University, Graduate School of Medicine, Lecturer, 大学院・医学研究院, 講師 (00202763)
SAKAMOTO Akemi  Chiba University, Graduate School of Medicine, Assistant Prof., 大学院・医学研究院, 助手 (90359597)
FUJIMURA Liza  Chiba University, Graduate School of Medicine, Assistant Prof., バイオメディカル研究センター, 助手 (30376363)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2005: ¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 2004: ¥8,500,000 (Direct Cost: ¥8,500,000)
KeywordsBcl6 / somatic hypermutation / ADAR1 / immunoglobulin class-switch region / germinal center B cells / memory B cells / class-switch / gene-deficient mice
Research Abstract

Bcl6 is highly expressed in germinal center B cells and is essential for development of high affinity memory B cells. Bcl6 functions as a sequence specific transcriptional repressor by recruiting a histone deacetylase complex. However, the role for Bcl6 in somatic hypermutation (SHM) of immunoglobulin genes is largely unknown. Here we show that SHM with two hot spots was detected in the immunoglobulin class-switch region of various cells from Bcl6-deficient mice. These hot spot SHMs were generated by conversion of adenine to guanine. Adenosine deaminase acting on RNA-1 (ADAR1) mRNA was overexpressed in various cells from Bcl6-deficient mice but repressed in lck-Bcl6 transgenic mice, and three Bcl6-binding sequences were identified in the promoter region of the ADAR1 gene, indicating that ADAR1 is a molecular target of Bcl6. Overexpression of ADAR1 triggered the SHMs in normal cells. Furthermore, histone acetylation was observed in the hot spot region of Bcl6-deficient cells whereas Bcl6 bound near the region to deacetylate regional histones in normal cells. Thus, ADAR1 can induce SHM in germ line DNA with chromatin modifications, and Bcl6 inhibits the ADAR1-induced SHM especially in germinal center B cells.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (25 results)

All 2005 2004

All Journal Article (24 results) Book (1 results)

  • [Journal Article] Pkdl regulates immortalized proliferation of renal tubular epithelial cells through induction of P53 and activation of JNK.2005

    • Author(s)
      Nishio, S., et al.
    • Journal Title

      J. Clin. Invest. 115

      Pages: 910-918

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A role for c-Fos/AP-1 in B lymphocyte terminal differentiation.2005

    • Author(s)
      Ohkubo, Y., et al.
    • Journal Title

      J. Immunol. 174

      Pages: 7703-7710

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] DNA polymerase (theta) contributes to the generation of C/G mutations during somatic hypermutation of Ig genes.2005

    • Author(s)
      Masuda, K., et al.
    • Journal Title

      Proc. Natl. Acad. Sci. USA. 102

      Pages: 13986-13991

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through induction of P53 and activation of JNK.2005

    • Author(s)
      Nishio, S., Hatano, M., Nagata, M., Horie, S., Koike, T., Tokuhisa, T., Mochizuki, T.
    • Journal Title

      J.Clin.Invest. 115

      Pages: 910-918

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A role for c-Fos/AP-1 in B lymphocyte terminal differentiation.2005

    • Author(s)
      Ohkubo, Y., Arima, M., Arguni, E., Okada, S., Yamashita, K., Asari, S., Obata, S., Sakamoto, A., Hatano, M., O-Wang, J., Ebara, M., Saisho, H., Tokuhisa, T.
    • Journal Title

      J.Immunol. 174

      Pages: 7703-7710

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] DNA polymerase (theta) contributes to the generation of C/G mutations during somatic hypermutation of Ig genes.2005

    • Author(s)
      Masuda, K., Ouchida, R., Takeuchi, A., Saito, T., Koseki, H., Kawamura, K., Tagawa, M., Tokuhisa, T., Azuma, T., Jiyang O-Wang, J.
    • Journal Title

      Proc.Natl.Acad.Sci.USA. 102

      Pages: 13986-13991

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Abnormal erythroid differentiation in neonatal Bcl6-deficient mice.2005

    • Author(s)
      Asari, S., et al.
    • Journal Title

      Exp.Hematol. 33

      Pages: 26-34

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through induction of P53 and activation of JNK.2005

    • Author(s)
      Nishio, S., et al.
    • Journal Title

      J.Clin.Invest. 115

      Pages: 910-918

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Targeted disruption of TGF-β-Smad3 signaling leads to enhanced neointimal hyperplasia with diminished matrix deposition in response to vascular injury.2005

    • Author(s)
      Kobayashi, K., et al.
    • Journal Title

      Circ.Res. 96

      Pages: 904-912

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A role for c-Fos/AP-1 in B lymphocyte terminal differentiation.2005

    • Author(s)
      Ohkubo, Y., et al.
    • Journal Title

      J.Immunol. 174

      Pages: 7703-7710

    • Related Report
      2005 Annual Research Report
  • [Journal Article] The pro-atherogenic cytokine interleukin-18 induces CXCL16 expression in rat aortic smooth muscle cells via MyD88,IRAK,TRAF6,c-Src,PI3K,Akt,JNK, and AP-1 signaling.2005

    • Author(s)
      Chandrasekar, B., et al.
    • Journal Title

      J.Biol.Chem. 280

      Pages: 26263-26277

    • Related Report
      2005 Annual Research Report
  • [Journal Article] DNA polymerase (theta) contributes to the generation of C/G mutations during somatic hypermutation of Ig genes.2005

    • Author(s)
      Masuda, K., et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA. 102

      Pages: 13986-13991

    • Related Report
      2005 Annual Research Report
  • [Journal Article] β-galactosidase of ROSA26 mice is a useful marker for detecting the definitive erythropoiesis after stem cell transplantation.2004

    • Author(s)
      Asari, S., et al.
    • Journal Title

      Transplantation 78

      Pages: 516-523

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Bc16 acts as an amplifier for the generation and proliferative capacity of central memory CD8^+ T cells.2004

    • Author(s)
      Ichii, H., et al.
    • Journal Title

      J. Immunol. 173

      Pages: 883-891

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Role of autophagy during the early neonatal starvation period.2004

    • Author(s)
      Kuma, A., et al.
    • Journal Title

      Nature 432

      Pages: 1032-1036

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Abnormal erythroid differentiation in neonatal Bcl6-deficient mice.2004

    • Author(s)
      Asari, S., Sakamoto, A., Okada, S., Ohkubo, Y, Arima, M., Hatano, M., Kuroda, K., Tokuhisa, T.
    • Journal Title

      Transplantation 78

      Pages: 516-523

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Bcl6 acts as an amplifier for the generation and proliferative capacity of central memory CD8^+ T cells.2004

    • Author(s)
      Ichii, H., Sakamoto, A., Kuroda, Y., Tokuhisa T.
    • Journal Title

      J.Immunol. 173

      Pages: 883-891

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Role of autophagy during the early neonatal starvation period.2004

    • Author(s)
      Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., Mizushima, N.
    • Journal Title

      Nature 432

      Pages: 1032-1036

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Role of autophagy during the early neonatal starvation period.2004

    • Author(s)
      Kuma, et al.
    • Journal Title

      Nature 432

      Pages: 1032-1036

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Effect of c-fos overexpression on development and proliferation of peritoneal R cells2004

    • Author(s)
      Mori, et al.
    • Journal Title

      Int.Immunol. 16

      Pages: 1477-1486

    • Related Report
      2004 Annual Research Report
  • [Journal Article] BAZF is required for activation of naive CD4 T cells by TCR-triggering2004

    • Author(s)
      Takamori, et al.
    • Journal Title

      Int.Immunol. 16

      Pages: 1439-1449

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Bcl6 acts as an amplifier for the generation and proliferative capacity of central memory CD8^+ T cells.2004

    • Author(s)
      Ichii, et al.
    • Journal Title

      J.Immunol. 173

      Pages: 883-891

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Early erythropoiesis in the bone mrrow and spleen after stem cell transplantation.2004

    • Author(s)
      Asari, et al.
    • Journal Title

      Transplantation 78

      Pages: 516-523

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Impaired lymphocyte development and function in Clast5/Stra13/DEC1 transgenic mice.2004

    • Author(s)
      Seimiya, et al.
    • Journal Title

      Eur.J.Immunol. 34

      Pages: 1322-1332

    • Related Report
      2004 Annual Research Report
  • [Book] Strategies for disease control.2005

    • Author(s)
      Arguni, E., et al.
    • Total Pages
      216
    • Publisher
      Elsevier
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary

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Published: 2004-04-01   Modified: 2016-04-21  

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