Plasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs

Abstract

The genomic loci associated with B cell differentiation that are subject to transcriptional and epigenetic regulation in vivo are not well defined, leaving a gap in our understanding of the development of humoral immune responses. Here, using an in vivo T cell independent B cell differentiation model, we define a cellular division-dependent cis-regulatory element road map using ATAC-seq. Chromatin accessibility changes correlate with gene expression and reveal the reprogramming of transcriptional networks and the genes they regulate at specific cell divisions. A subset of genes in naive B cells display accessible promoters in the absence of transcription and are marked by H3K27me3, an EZH2 catalyzed repressive modification. Such genes encode regulators of cell division and metabolism and include the essential plasma cell transcription factor Blimp-1. Chemical inhibition of EZH2 results in enhanced plasma cell formation, increased expression of the above gene set, and premature expression of Blimp-1 ex vivo. These data provide insights into cell-division coupled epigenetic and transcriptional processes that program plasma cells.

Influenza-specific effector memory B cells predict long-lived antibody responses to vaccination in humans

“…B cell differentiation into ASCs is known to be epigenetically regulated in a division dependent manner 56, 57 and cell cycle arrest facilitates terminal immune cell differentiation. 58 Top up-regulated TFs in the PR analysis of the day 7 antigen-specific T-bet hi over T-bet lo Bmem network, include SOX5 and E2F7 (Figure 2L), and these TFs inhibit cell proliferation and/or effect cell cycle arrest.…”

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

“…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]. Of note is that the negative control compound for UNC1999, UNC2400, had similar effects as UNC1999 ( Figure 6) implicating off-target effects of UNC1999.…”

Cxcr4 desensitization is an essential regulatory mechanism controlling the extra-follicular B cell response

“…under preparation). In line with that hypothesis, recent studies on human and mouse B cells revealed that PC differentiation is coupled to division-dependent DNA demethylation and PC gene regulation [30][31][32] . Together with the results presented here, these observations suggest that the enhanced Cxcl12/Cxcr4 signaling mediated by the gain of function of the receptor together with the enhanced availability of its ligand, may contribute to a deep imprinting of the B cells that could partly explain the phenotypes observed.…”