EZH2 Represses the B Cell Transcriptional Program and Regulates Antibody-Secreting Cell Metabolism and Antibody Production

Abstract

Epigenetic remodeling is required during B cell differentiation. However, little is known about the direct functions of epigenetic enzymes in Ab-secreting cells (ASC) in vivo. In this study, we examined ASC differentiation independent of T cell help and germinal center reactions using mice with inducible or B cell-specific deletions of Following stimulation with influenza virus or LPS,-deficient ASC poorly proliferated and inappropriately maintained expression of inflammatory pathways, B cell-lineage transcription factors, and Blimp-1-repressed genes, leading to fewer and less functional ASC. In the absence of EZH2, genes that normally gained histone H3 lysine 27 trimethylation were dysregulated and exhibited increased chromatin accessibility. Furthermore, EZH2 was also required for maximal Ab secretion by ASC, in part due to reduced mitochondrial respiration, impaired glucose metabolism, and poor expression of the unfolded-protein response pathway. Together, these data demonstrate that EZH2 is essential in facilitating epigenetic changes that regulate ASC fate, function, and metabolism.

Identifying novel B-cell targets for chronic inflammatory autoimmune disease by screening of chemical probes in a patient-derived cell assay

“…Accordingly, we saw a marked reduction in the accumulation of B cells in the presence of WDR5 inhibitor OICR9429 (Figure 3b), while the effect on proliferation as indicated by Ki67 expression was marginal (Figure 4). The transcriptional repressor EZH2 is required for maximal antibody secretion [31] and is overexpressed in SLE leukocytes [32]. While we show reduced antibody secretion in presence of the EZH2 inhibitor UNC1999 (Figure 3b), we see very little effects on proliferation (Figure 4) in contrast to other studies [33,34].…”

A dichotomy in association of core transcription factors and gene regulation during the activated B-cell to plasmablast transition

“…In order to regulate gene expression, BLIMP1 recruits epigenetic coregulators. 17, 21–27 While an important role for EZH2 has been identified, 17, 25 the relative contribution of G9A and in particular G9A in human cells has not been extensively studied. 66 Small molecule inhibitors of epigenetic regulators provide tool compounds for exploring functional biology.…”

The histone methyltransferase DOT1L is essential for humoral immune responses

“…Specifically, we determined whether conditional deletion of DOT1L would result in a reduction of global H3K79me2 in B cell subsets ( Figure S2A). As a control, we also tested polycomb repressive complex 2 (PRC2)-mediated H3K27me3, which has also been shown to be an important regulator of B cell biology (Beguelin et al, 2013;Caganova et al, 2013;Guo et al, 2018;Su et al, 2003).…”