DNA methylation profiling in human B cells reveals immune regulatory elements and epigenetic plasticity at Alu elements during B-cell activation

Abstract

Memory is a hallmark of adaptive immunity, wherein lymphocytes mount a superior response to a previously encountered antigen. It has been speculated that epigenetic alterations in memory lymphocytes contribute to their functional distinction from their naive counterparts. However, the nature and extent of epigenetic alterations in memory compartments remain poorly characterized. Here we profile the DNA methylome and the transcriptome of B-lymphocyte subsets representing stages of the humoral immune response before and after antigen exposure in vivo from multiple humans. A significant percentage of activation-induced losses of DNA methylation mapped to transcription factor binding sites. An additional class of demethylated loci mapped to Alu elements across the genome and accompanied repression of DNA methyltransferase 3A. The activation-dependent DNA methylation changes were largely retained in the progeny of activated B cells, generating a similar epigenetic signature in downstream memory B cells and plasma cells with distinct transcriptional programs. These findings provide insights into the methylation dynamics of the genome during cellular differentiation in an immune response.

Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs

“…17 We showed that treatment with GSK-J4 leads to a reduction in BCL6 protein levels, perhaps through inhibition of BCR signaling. Indeed, a recent study suggested that KDM6B promotes the survival of DLBCL cells.…”

“…eration. 16,17 Aberrant histone methylation or demethylation can result in inappropriate transcriptional silencing, which can drive chemoresistance and malignant transformation. 18 An analysis of histone methylation in DLBCL samples suggests that aberrant methylation increases with disease aggressiveness.…”

DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID

“…We previously observed significant loss of DNA methylation in human GCB (Lai et al, 2013; Shaknovich et al, 2011). We hypothesized that AID would be at least partly responsible for this decrease.…”

“…DNA methylation is understood to play a key role in gene imprinting, X chromosome inactivation, and regulation of gene expression specific to tissue identity, developmental stage and cell lineage (Bird, 2002; Jones and Takai, 2001). Changes in the DNA methylome mark specific stages of B cell ontogeny and play an important role in B cell lymphomagenesis (De et al, 2013; Jeong et al, 2014; Kulis et al, 2012; Lai et al, 2013; Mayle et al, 2014; Shaknovich et al, 2010; Zhang et al, 2014). The GC stage of B cell development is associated with a proliferative burst, affinity maturation of B cells with associated SHM and CSR, all of which contribute to adaptive immune response and determine antibody diversity (Klein and Dalla-Favera, 2008), but the contribution of the methylome to these processes is not clearly defined.…”

“…The transition from NB to GCB, critical for affinity maturation and generation of an improved, long-lasting immune response, is accompanied by marked demethylation of the genome and more heterogeneous DNA methylation patterning (Lai et al, 2013; Shaknovich et al, 2011). The mechanisms of these modifications of the methylome remain poorly understood and, therefore, we set out to understand how these changes arise in B cells.…”