Elucidation of the epigenetic regulation of the antigen receptor gene rearrangement

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17590246
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: AGATA Yasutoshi Kyoto University, HMRO, Grad. School of Med., Associate Professor, 医学研究科, 科学技術振興助教授 (60263141)
• Co-Investigator(Kenkyū-buntansha): SAKAMOTO Shuji Kyoto University, HMRO, Grad. School of Med., Assistant Professor, 医学研究科, 科学技術振興助手 (80397546)
• Project Period (FY): 2005 – 2006
• Keywords: gene / genome / regulation of expression / development / differentiation / immunology

Research Abstract

1)Analysis of the factors involved in chromatin structural changes induced by E2A
When E2A was ectopically expressed with RAG1/2 in BOSC 23 cells that are highly efficient in transfection, germline transcription as well as rearrangement were induced in the endogenous immunoglobulin κ locus. E2A was found to associate with the recombination target regions and increase acetylation of histone H3 and H4. Among several histone acetyltransferases examined, p300/CBP were specifically recruited to the target sites by E2A. Consistent with this, overexpression of p300/CBP together with E2A resulted in increased histone acetylation, germline transcription and rearrangement. Conversely, down-regulation of endogenous p300/CBP by siRNA led to reduction of histone acetylation, germline transcription and rearrangement. Based on these observations, E2A was found to recruit p300/CBP to the recombination target regions and induce rearrangement by opening the chromatin structure through the increase of his tone acetylation.
2)Analysis of the nuclear mechanisms and physiological roles for allelic exclusion
Allelic exclusion of the antigen receptor genes is a phenomenon, in which a productive rearrangement takes place only on one allelic chromosome, and ensures that an individual lymphocyte expresses only one antigen receptor. It has been postulated for the possible mechanism underlying allelic exclusion that, once a productive rearrangement has been generated, a negative feedback signal mediated by the antigen receptor prevents continued rearrangement. We found that E2A promotes T cell receptor β gene rearrangement by directly binding to target gene segments to increase chromatin accessibility in a dosage-sensitive manner. Feedback signaling abrogates E2A binding, leading to a decline in accessibility. Conversely, enforced expression of E2A induces rearrangement by overriding the feedback inhibition. Thus, the abundance of E2A is rate limiting in locus activation, and feedback signaling down-regulates E2A activity to ensure allelic exclusion.

Research Products

• [Journal Article] Spontaneous Large-scale Lymphoid Neogenesis and Balanced Autoimmunity versus Tolerance in the Stomach of H^+/K^+-ATPase-reactive TCR Transgenic Mouse. (2006)
  • Author(s): Katakai, T., Nomura, T., Gonda, H., Sugai, M., Agata, Y., Nishio, A., Masuda, T., Sakaguchi, S., Shimizu, A.
  • Journal Title: J. Immunol. 177 Pages: 7858-7867
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Spontaneous Large-scale Lymphoid Neogenesis and Balanced Autoimmunity versus Tolerance in the Stomach of H+/K+-ATPase-reactive TCR Transgenic Mouse. (2006)
  • Author(s): Katakai, T., Nomura, T., Gonda, H., Sugai, M., Agata, Y., Nishio, A., Masuda, T., Sakaguchi, S., Shimizu, A.
  • Journal Title: J. Immunol. 177 Pages: 7858-7867
  • Description: 「研究成果報告書概要(欧文)」より