Enhancer of zeste homolog 2 (EZH2) has been shown to regulate early B cell development and the differentiation of antibody secreting cells (ASCs). We have previously demonstrated increased EZH2 expression in peripheral blood mononuclear cells isolated from lupus patients, and that pharmacological inhibition of EZH2 alleviates lupus-like disease in mouse models. In this study, we generated a conditional knockout mouse to examine the effect of EZH2 deficiency in B cells in the MRL/lpr lupus-prone mouse. We show that Ezh2 deletion in B cells significantly decreased autoantibody production and improved glomerulonephritis. B cell development was altered in the bone marrow and spleen in EZH2-deficient mice. Differentiation of ASCs was impaired. Single cell RNA sequencing showed that XBP1, a key transcription factor in B cell development, is downregulated in the absence of EZH2. Inhibiting XBP1 in vitro impairs ASC development similar to EZH2-deficient mice. Single cell B cell receptor RNA sequencing revealed defective immunoglobulin class switch recombination in EZH2- deficient mice. In human lupus B cells, we observed a strong correlation between EZH2 and XBP1 mRNA expression levels. Taken together, our results suggest that EZH2 overexpression in B cells contributes to disease pathogenesis in lupus.
Lay Summary Epigenetics refers to the mechanisms that regulate gene expression. DNA methylation is a key epigenetic mechanism that is dysregulated in lupus cells. We have previously revealed a central role for EZH2, a key epigenetic modifier, in modulating epigenetic changes in lupus. We have shown that lupus immune cells, including T and B lymphocytes, overexpress EZH2. In this study we generated a mouse model to delete the gene encoding EZH2 in B cells. We show that EZH2-deficient lupus-prone mice are significantly protected from lupus-like disease, with a reduction in autoantibody production and renal involvement. EZH2 deficiency impair B cell development by downregulating XBP1 which plays an important role in B cell differentiation.
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