Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

Abstract

B cells are the center of humoral immunity and produce Abs to protect against foreign Ags. B cell defects lead to diseases such as leukemia and lymphomas. Histone arginine methylation is important for regulating gene activation and silencing in cells. Although the process commonly exists in mammalian cells, its roles in B cells are unknown. To explore the effects of aberrant histone arginine methylation on B cells, we generated mice with a B cell–specific knockout of PRMT7, a member of the methyltransferases that mediate arginine methylation of histones. In this article, we showed that the loss of PRMT7 led to decreased mature marginal zone B cells and increased follicular B cells and promoted germinal center formation after immunization. Furthermore, mice lacking PRMT7 expression in B cells secreted low levels of IgG1 and IgA. Abnormal expression of germinal center genes (i.e., Bcl6, Prdm1, and Irf4) was detected in conditional knockout mice. By overexpressing PRMT7 in the Raji and A20 cell lines derived from B cell lymphomas, we validated the fact that PRMT7 negatively regulated Bcl6 expression. Using chromatin immunoprecipitation–PCR, we found that PRMT7 could recruit H4R3me1 and symmetric H4R3me2 to the Bcl6 promoter. These results provide evidence for the important roles played by PRMT7 in germinal center formation.

Arginine methylation catalyzed by PRMT1 is required for B cell activation and differentiation

“…The activity of the transcription factor E2F-1, for example, varies depending on the relative amounts of PRMT1 and PRMT5, which compete for access to the same methylation site, promoting apoptosis and proliferation, respectively 36 . In addition to the role of PRMT1 in GC formation reported here, PRMT7 has been shown to repress transcription of Bcl-6 via H4R3 methylation in its promoter 37 . Deletion of Prmt7 in B cells increases Bcl6 expression, promoting GC development and repressing Irf4 and Prdm1 , genes that are required for plasma cells differentiation 37 .…”

“…In addition to the role of PRMT1 in GC formation reported here, PRMT7 has been shown to repress transcription of Bcl-6 via H4R3 methylation in its promoter 37 . Deletion of Prmt7 in B cells increases Bcl6 expression, promoting GC development and repressing Irf4 and Prdm1 , genes that are required for plasma cells differentiation 37 . Conceivably, any interplay between PRMT1 and PRMT7 in which one affected the activity of the other, could contribute to the in vivo B-cell phenotype observed here.…”

Arginine Methylation by PRMT1 Regulates Muscle Stem Cell Fate

“…Mice with whole-body knockout of PRMT6 are viable; however, the mouse embryo fibroblasts undergo premature senescence (17). Type III enzyme PRMT7 (2) is required in mice for B cell differentiation by controlling germinal center formation (18) and for muscle stem cell regeneration (19). PRMT8-deficient mice have motor coordination defects, and PRMT8 was characterized as an arginine methyltransferase and a phospholipase in Purkinje cells (20).…”

Caenorhabditis elegans PRMT-7 and PRMT-9 Are Evolutionarily Conserved Protein Arginine Methyltransferases with Distinct Substrate Specificities

“…Based on reports that the expression level of PRMT7 can affect SDMA levels in mammalian histones 11,12,15,16,30 , we also asked if the active C. elegans PRMT-7 enzyme could catalyze dimethylation of arginine species. However, as shown in the expanded view of the amino acid analysis shown in Fig.…”

“…While PRMT9 appears to have a major role in the regulation of alternative splicing 5 , for PRMT7 the situation is more complex. Recent studies have shown that PRMT7 is involved in preserving satellite cell regenerative capacity 10 , regulation of germinal center formation 11 , induction of the epithelial-to-mesenchymal transition 12 , and bone development 13 , in addition to roles in cancer such as the promotion of breast cancer metastasis through MMP9 expression 14 . However, it has not yet been possible to connect these phenomena to the specific enzymatic action of PRMT7.…”