LSD1 Cooperates with Noncanonical NF-kappa B Signaling to Regulate Marginal Zone B Cell Development

摘要

Marginal zone B cells (MZB) are a mature B cell subset that rapidly respond to blood-borne pathogens. Although the transcriptional changes that occur throughout MZB development are known, the corresponding epigenetic changes and epigenetic modifying proteins that facilitate these changes are poorly understood. The histone demethylase LSD1 is an epigenetic modifier that promotes plasmablast formation, but its role in B cell development has not been explored. In this study, a role for LSD1 in the development of B cell subsets was examined. B cell-conditional deletion of LSD1 in mice resulted in a decrease in MZB whereas follicular B cells and bone marrow B cell populations were minimally affected. LSD1 repressed genes in MZB that were normally upregulated in the myeloid and follicular B cell lineages. Correspondingly, LSD1 regulated chromatin accessibility at the motifs of transcription factors known to regulate splenic B cell development, including NF-kappa B motifs. The importance of NF-kappa B signaling was examined through an ex vivo MZB development assay, which showed that both LSD1-deficient and NF-kappa B-inhibited transitional B cells failed to undergo full MZB development. Gene expression and chromatin accessibility analyses of in vivo- and ex vivo-generated LSD1-deficient MZB indicated that LSD1 regulated the downstream target genes of noncanonical NF-kappa B signaling. Additionally LSD1 was found to interact with the noncanonical NF-kappa B transcription factor p52. Together, these data reveal that the epigenetic modulation of the noncanonical NF-kappa B signaling pathway by LSD1 is an essential process during the development of MZB.