Trends in Immunology
Volume 41, Issue 1, January 2020, Pages 46-60
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Review
From Loops to Looks: Transcription Factors and Chromatin Organization Shaping Terminal B Cell Differentiation

https://doi.org/10.1016/j.it.2019.11.006Get rights and content

Highlights

  • B cell differentiation underlies the development of the vertebrate humoral immune response, based on the production of highly diverse antibodies that can recognize and eliminate virtually any antigen.

  • B lymphocyte generation is strictly regulated at the transcriptional level. During terminal differentiation, B cells undergo dramatic changes in their gene transcriptional programs to generate germinal center B cells, plasma cells, and memory B cells.

  • Transcription factor networks and the epigenetic machinery are involved at all differentiation steps of B cell development.

  • Recent technical advances to study 3D chromatin conformation are providing unprecedented opportunities for gaining mechanistic insight into mammalian B lymphocyte biology.

  • Increasing evidence suggests that germinal center reactions and terminal B cell differentiation require the integrated coordination of 3D chromatin remodeling and B cell transcription factor activities as well as epigenetic modifications.

B lymphopoiesis is tightly regulated at the level of gene transcription. In recent years, investigators have shed light on the transcription factor networks and the epigenetic machinery involved at all differentiation steps of mammalian B cell development. During terminal differentiation, B cells undergo dramatic changes in gene transcriptional programs to generate germinal center B cells, plasma cells and memory B cells. Recent evidence indicates that mature B cell formation involves an essential contribution from 3D chromatin conformations through its interplay with transcription factors and epigenetic machinery. Here, we provide an up-to-date overview of the coordination between transcription factors, epigenetic changes, and chromatin architecture during terminal B cell differentiation, focusing on recent discoveries and technical advances for studying 3D chromatin structures.

Section snippets

B Lymphocyte Development

B cell differentiation underlies the development of the vertebrate humoral immune response, based on the production of highly diverse antibodies that can recognize and eliminate virtually any antigen. Antibody diversity is achieved at two stages during B cell differentiation. The first is V(D)J recombination in early B cell precursors during bone marrow differentiation and involves the combinatorial rearrangement of variable (V), diversity (D), and joining (J) coding segments of immunoglobulin

3D Chromatin Conformation and Its Impact on Gene Regulation

Every nucleated human cell contains approximately 2 m of linear DNA encompassing all of the genes that shape our being. This DNA, which is the same in almost every cell, is packed into a nucleus measuring only a few microns in diameter; this packaging is not random, and the specific folding of DNA plays a fundamental role in the regulation of gene expression. In some cases, the folded DNA conformation brings promoters of coregulated genes or regulatory elements, such as enhancers, into physical

Recent Technical Advances in Studying 3D Chromatin Conformation

No cell activity or function can be understood without considering the time-dependent 3D organization of the genome in the nucleus. The explosion of chromosome conformation capture (3C)-based methods (see below) over the past decade has complemented and enriched classical microscopy analysis and has positioned nuclear genome organization as one of the hottest fields in molecular biology. The most common 3C-based technologies have allowed and are allowing investigators to reveal the general

Biological Role of Nuclear Compartmentalization

State-of-the-art technologies based on chromatin conformation approaches at highest resolution, either by sequencing or by imaging, have revealed stratified levels of genome organization and compartmentalization. Briefly, at the chromosome scale, genomic regions can be divided into two main compartments: A, which contains active chromatin and is located in the inner part of the nucleus; and B, which comprises heterochromatic regions located close to the nuclear lamina [22]. In compartments, the

Chromatin Conformation Changes during the GC Reaction

Antigen recognition by naïve B cells triggers dramatic phenotypic and gene expression changes and their differentiation into GC B cells. This developmental program involves intense proliferation, increases in nucleus size, and major genetic and epigenetic changes in GC B cells [3] (Figure 4). Using 3C, 4C, and Hi-C technologies, two recent studies revealed that human and mouse primary B cells undergo progressive chromatin decondensation on antigen recognition and during the GC reaction, leading

Chromatin Conformation Changes in PCs

The spatial conformation of PC chromatin has been studied since the early part of the last century. Cajal drew faithful and characteristic chromatin patterns reminiscent of a cartwheel [70]. This distinctive feature is in part acquired as a result of the transformation of active chromatin (euchromatin) into inactive chromatin (heterochromatin), a process undergone by most terminally differentiating cells [71] (Figure 4). In general, the initiation of differentiation and the establishment of a

Chromatin Conformation Changes in Memory B Cells

Memory B cells constitute a heterogeneous population of long-lived cells that self-maintain in an antigen-independent fashion and exert a rapid and robust antibody response to subsequent antigen exposure [92,93]. Recently, although pending peer review, using Hi-C and many other omics approaches one study reported that the genome architectures of naïve and memory B cells might be closely related compared with GC B cells or PCs [41]. Accordingly, microarray experiments of purified murine naïve,

Concluding Remarks

The recent explosive growth in techniques for studying chromatin conformation places the B cell field in a position to advance our understanding of how a proper humoral response is generated. However, further studies are needed to decipher the precise mechanisms involved in regulating and enacting specific and dynamic genome reorganization during terminal B cell differentiation (see Outstanding Questions). Recent evidence establishes a strong relationship between nuclear architecture, TFs, the

Acknowledgments

We thank Simon Bartlett for English editing. We thank CERCA Programme/Generalitat de Catalunya for institutional support. This work was supported by AGAUR project number 2017SGR149 of the Catalan Government (Generalitat de Catalunya). M.P. is funded by Ministerio de Economía y Competitividad (MINECO) project number SAF2017-87990-R. B.M.J. is funded by Spanish Ministry of Science, Innovation, and Universities (MICINN) project number RTI2018-094788-A-I00 and by La Caixa Banking Foundation Junior

Glossary

Activation-induced cytidine deaminase (AID)
enzyme highly expressed in GC B cells, with a mutagenic role; essential for SHM and CSR processes.
Affinity maturation
process whereby Tfh cell-activated B cells fine-tune/improve antibody affinity for a given antigen during the humoral immune response.
ATAC-seq
molecular biology method used to evaluate genome-wide chromatin accessibility.
B cell receptor (BCR)
transmembrane protein comprising a membrane-bound Ig and associated peptides. On antigen

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