Epigenetic Regulation of B Cell Memory Formation: A Poised Model for B Cell Epigenetic Reprograming

Abstract

The formation of B cell immunological memory happens after the first encounter with a pathogen. At the germinal center (GC), B cells experience complex transcriptional and epigenetic transitions to differentiate into memory B cells (MBCs) and plasma cells (PCs). In particular, the differentiation of GC B cells into MBCs has been poorly understood, and no clear conclusions on the signals and transcription factors leading to this cell fate have been identified. Recent discoveries in epigenetics and immune memory have elucidated the essential role of epigenetic regulators in establishing the memory B cell (MBC) fate. DNA methylation regulators, histone modifiers, noncoding RNAs (ncRNAs), and chromatin remodelers orchestrate a dynamic reprograming of the MBC phenotype. Positive and negative epigenetic regulators of the B cell program collaborate at each differentiation stage and allow for complex chromatin topology rearrangements and dynamic exposure to transcription and translation. Following MBC fate determination at the GC, the acquired epigenetic modifications induce a poised regulatory state where genes are epigenetically marked to remain transcriptionally inactive, but primed for rapid activation upon stimuli. Thus, a poised epigenetic control over gene expression governs MBC formation and a novel model of epigenetic reprograming is proposed. This model provides a novel perspective on how the B cell fate is determined in the GC and memory is formed, offering insights for improved vaccination and therapeutical approaches.

Keywords: B cell fate determination; B cell memory; epigenetics; germinal center; memory B cells; poised genes.

Figure 1

Poised model of epigenetic reprograming in B cell memory formation. Representative model of the main transcription, epigenetic, and posttranscriptional regulators of memory B cell differentiation. Positive and negative epigenetic regulators of germinal center B cells, memory B cells, and plasma cells establish a dynamic environment, where transcription regulator genes are expressed in a poised manner. As such, chromatin modifiers, posttranscriptional regulators and a three-dimensional reorganization of the genome promotes rapid transcriptional changes and the formation of a dynamic switch. The presented model focuses on the epigenetic regulators establishing and repressing the memory B cell phenotype. Four different types of epigenetic regulators are presented, labeled 1–4 as stated in the figure legend. AID, activation-induced cytidine deaminase; ARID1A, AT-rich interactive domain 1A; BACH2, broad complex-tramtrack-bric a brac and Cap'n'collar homology 2; BCL6, B cell lymphoma 6; BLIMP1, B lymphocyte-induced maturation protein 1; BRWD1, bromodomain and WD repeat-containing 1; CCR6, chemokine receptor 6; CREBBP, CREB-binding protein; COPDA1, chronic obstructive pulmonary disease A1; CXCR4, C-X-C chemokine receptor type 4; DNMT1, DNA methyltransferase 1; DNMT3a, DNA methyltransferase 3a; DNMT3b, DNA methyltransferase 3b; EZH2, enhancer of zest 2; GC, germinal center; HDAC3, histone deacetylase 3; HELLS, lymphoid-specific helicase; HHEX, hematopoietically-expressed homeobox; IRF4, interferon-regulatory factor 4; KMT2D, lysine methyltransferase 2d; MBC, memory B cell; miR, micro-RNA; MOZ, monocytic leukemia zinc finger; PC, Plasma cell; TCL6, T-cell leukemia/lymphoma 6; TET proteins, ten-eleven-translocation proteins; Tfh cell, T follicular helper cell; TUNAR, TCL1 upstream neural differentiation-associated RNA. Figure created by the author, inspired by references [5] and [38]. Illustrations taken from NIAID NIH BIOART Source (bioart.niaid.nih.gov/bioart/).