A role of Bcl6 in regulation of somatic hypermutation in the immunoglobulin gene

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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, a role for Bcl6 in induction of somatic hypermutation in germinal center B cells is not known. When we examined mutation frequencies in the Ig class-switch region and the c-myc region of IgG1 B cells derived from Bcl6-deficient mice, the frequencies in Bcl6-deficient IgG1 B cells were higher than those in wild type IgG1 B cells. These mutations were mainly generated by conversion of adenine to guanine. RNA-editing adenosine deaminase (ADAR) family converts adenosine of pre-mRNA into inosine, which is subsequently translated as guanosine, and ADAR1 mRNA among ADAR family was overexpressed in various cells from Bcl6-deficient mice. The promoter analysis revealed that ADAR1 is a molecular target of Bcl6. Furthermore, the exogenous ADAR1 increased frequency of point mutations from adenine to guanine in those regions of wild type IgG1 B cells. Since ADAR1 mRNA is detected in germinal center B cells in spite of high Bcl6 expression, ADAR1 may contribute adenine-targeted somatic hypermutation in germinal center B cells.