Opposing Roles for the Related ETS-Family Transcription Factors Spi-B and Spi-C in Regulating B Cell Differentiation and Function

Abstract

Generation of specific antibodies during an immune response to infection or vaccination depends on the ability to rapidly and accurately select clones of antibody-secreting B lymphocytes for expansion. Antigen-specific B cell clones undergo the cell fate decision to differentiate into antibody-secreting plasma cells, memory B cells, or germinal center B cells. The E26-transformation-specific (ETS) transcription factors Spi-B and Spi-C are important regulators of B cell development and function. Spi-B is expressed throughout B cell development and is downregulated upon plasma cell differentiation. Spi-C is highly related to Spi-B and has similar DNA-binding specificity. Heterozygosity for Spic rescues B cell development and B cell proliferation defects observed in Spi-B knockout mice. In this study, we show that heterozygosity for Spic rescued defective IgG1 secondary antibody responses in Spib −/− mice. Plasma cell differentiation was accelerated in Spib −/− B cells. Gene expression, ChIP-seq, and reporter gene analysis showed that Spi-B and Spi-C differentially regulated Bach2, encoding a key regulator of plasma cell and memory B cell differentiation. These results suggest that Spi-B and Spi-C oppose the function of one another to regulate B cell differentiation and function.

Lineage‐instructive functions of the E26‐transformation‐specific‐family transcription factor Spi‐C in immune cell development and disease

“…PU.1 and Spi-B act as transcriptional activators, while Spi-C primarily represses target genes (Li et al, 2015;Schweitzer et al, 2006). Although PU.1 and Spi-B are functionally complementary, studies show that Spi-C antagonizes their actions at multiple stages of B cell development and function (Laramée et al, 2020;Soodgupta et al, 2019;Zhu et al, 2008). PU.1 and Spi-B activate genes including Nfkb1, Bach2, Syk, and Blnk during crucial stages of development and differentiation, whereas Spi-C represses these target genes (DeKoter et al, 2010;Laramée et al, 2020;Li et al, 2015).…”

“…Although PU.1 and Spi-B are functionally complementary, studies show that Spi-C antagonizes their actions at multiple stages of B cell development and function (Laramée et al, 2020;Soodgupta et al, 2019;Zhu et al, 2008). PU.1 and Spi-B activate genes including Nfkb1, Bach2, Syk, and Blnk during crucial stages of development and differentiation, whereas Spi-C represses these target genes (DeKoter et al, 2010;Laramée et al, 2020;Li et al, 2015). Chromatin immunoprecipitation-sequencing studies demonstrated that PU.1, Spi-B, and Spi-C interact as monomers primarily with single GGAA consensus motifs (Laramée et al, 2020;Solomon et al, 2015).…”

“…PU.1 and Spi-B activate genes including Nfkb1, Bach2, Syk, and Blnk during crucial stages of development and differentiation, whereas Spi-C represses these target genes (DeKoter et al, 2010;Laramée et al, 2020;Li et al, 2015). Chromatin immunoprecipitation-sequencing studies demonstrated that PU.1, Spi-B, and Spi-C interact as monomers primarily with single GGAA consensus motifs (Laramée et al, 2020;Solomon et al, 2015). The binding sites occupied by PU.1, Spi-B, and Spi-C are largely overlapping, although not identical (Laramée et al, 2020;Solomon et al, 2015).…”

“…Chromatin immunoprecipitation-sequencing studies demonstrated that PU.1, Spi-B, and Spi-C interact as monomers primarily with single GGAA consensus motifs (Laramée et al, 2020;Solomon et al, 2015). The binding sites occupied by PU.1, Spi-B, and Spi-C are largely overlapping, although not identical (Laramée et al, 2020;Solomon et al, 2015). Soodgupta et al recently showed that ectopic expression of Spi-C in pre-B cells caused significant changes in genome-wide chromatin binding of PU.1, while PU.1 expression remained constant, suggesting that Spi-C displaces PU.1 from binding sites (Soodgupta et al, 2019).…”

“…Together with work by Akilesh et al, these studies demonstrate that Spi-C is inducible by inflammatory stimuli in macrophages in sterile and disease environments. In B cells, Spi-C has been implicated in regulation of B cell development, antibody-generating responses, and suppression of pre-B cell receptor (BCR)-mediated proliferation (Bednarski et al, 2016;DeKoter et al, 2010;Laramée et al, 2020;Li et al, 2015;Zhu et al, 2008). Schweitzer et al (2006) first set out to examine the biological function of Spi-C in B cells.…”