Trends in Immunology
ReviewFrom Loops to Looks: Transcription Factors and Chromatin Organization Shaping Terminal B Cell Differentiation
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
References (105)
Long-range regulation of V(D)J recombination
Adv. Immunol.
(2015)AID targeting: old mysteries and new challenges
Trends Immunol
(2015)Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells
Immunity
(2002)Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4
Immunity
(2013)Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program
Immunity
(2002)- et al.
Terminal differentiation of lymphocytes depends on Blimp-1
Curr. Opin. Immunol.
(2007) Disruptions of topological chromatin domains cause pathogenic rewiring of gene–enhancer interactions
Cell
(2015)Multiscale 3D genome rewiring during mouse neural development
Cell
(2017)Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters
Cell
(2016)Architectural protein subclasses shape 3D organization of genomes during lineage commitment
Cell
(2013)
A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping
Cell
Higher-order inter-chromosomal hubs shape 3D genome organization in the nucleus
Cell
From cells to chromatin: capturing snapshots of genome organization with 5C technology
Methods
Myc regulates chromatin decompaction and nuclear architecture during B cell activation
Mol. Cell
Multi-tiered reorganization of the genome during B cell affinity maturation anchored by a germinal center-specific locus control region
Immunity
“Cat’s cradling” the 3D genome by the act of lncRNA transcription
Mol. Cell
A damage-independent role for 53BP1 that impacts break order and Igh architecture during class switch recombination
Cell Rep
YY1 controls Eμ-3′RR DNA loop formation and immunoglobulin heavy chain class switch recombination
Blood Adv
A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells
Blood
Zinc finger–IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell
Blood Adv
PU.1 and Spi-B are required for normal B cell receptor-mediated signal transduction
Immunity
Unravelling heterochromatin: competition between positive and negative factors regulates accessibility
Trends Genet
Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells
Immunity
Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1
Immunity
Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells
Immunity
Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire
Immunity
MicroRNA-155 regulates the generation of immunoglobulin class-switched plasma cells
Immunity
Repression of the transcription factor Bach2 contributes to predisposition of IgG1 memory B cells toward plasma cell differentiation
Immunity
Extremely long-range chromatin loops link topological domains to facilitate a diverse antibody repertoire
Cell Rep
Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions
Proc. Natl Acad. Sci. U. S. A.
Germinal centers
Annu. Rev. Immunol.
Mechanism and regulation of class switch recombination
Annu. Rev. Immunol.
A network model to describe the terminal differentiation of B cells
PLoS Comput. Biol.
Disruption of the Bcl6 gene results in an impaired germinal center formation
J. Exp. Med.
Repression of BCL-6 is required for the formation of human memory B cells in vitro
J. Exp. Med.
Generation of memory B cells and plasma cells in vitro
Science
Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution
Nat. Genet.
Chromatin topology and the regulation of antigen receptor assembly
Annu. Rev. Immunol.
New insights emerge as antibody repertoire diversification meets chromosome conformation
F1000Res
R loops in the regulation of antibody gene diversification
Genes (Basel)
The three-dimensional genome: regulating gene expression during pluripotency and development
Development
Comprehensive mapping of long-range interactions reveals folding principles of the human genome
Science
Spatial partitioning of the regulatory landscape of the X-inactivation centre
Nature
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Nature
Complex multi-enhancer contacts captured by genome architecture mapping
Nature
Single-cell Hi-C reveals cell-to-cell variability in chromosome structure
Nature
The second decade of 3C technologies: detailed insights into nuclear organization
Genes Dev
Capturing chromosome conformation
Science
High-resolution identification of balanced and complex chromosomal rearrangements by 4C technology
Nat. Methods
Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions
Nat. Genet.
Cited by (18)
Cellular specificity is key to deciphering epigenetic changes underlying Alzheimer's disease
2023, Neurobiology of DiseaseSingle cell cancer epigenetics
2022, Trends in CancerCitation Excerpt :These promising discoveries reinforce the potential of the aforementioned methodologies to study tumor cell epigenomes from a single cell perspective. The 3D structure of the genome is governed by chromosome conformation and folding within the nucleus and has been reported to have a significant role in the regulation of gene expression by, for instance, promoting the interaction of enhancers and promoters that regulates the expression of specific genes [80]. The nuclear architecture comprises chromosomal compartments that facilitate the emergence of trans-regulatory elements, long-range loops, topologically associating domains (TADs), and lamina-associated domains (LADs).
The epigenetic regulation of the germinal center response
2022, Biochimica et Biophysica Acta - Gene Regulatory MechanismsCitation Excerpt :More recently, with the development of imaging technologies for mapping 3D chromosome architecture such as genome-wide chromosomal conformation capture (Hi-C), it has been recognized that alterations of the 3D chromatin structures are increasingly implicated in the regulation of B cell differentiation and B cell related diseases [42–44]. Evidence indicates the integrated coordination of 3D chromatin reorganization and transcription factor networks provides an essential contribution to the generation of GC B cells and their terminal differentiation into plasma cells and memory B cells [44]. Once antigen recognized by naïve B cells, the 3D genome undergoes extensive compartment activation, leading to the phenotypic transition from resting B cells into GC B cells [33,42].
3D chromosomal architecture in germinal center B cells and its alterations in lymphomagenesis
2022, Current Opinion in Genetics and DevelopmentCitation Excerpt :The GC is composed of a dark zone where B cells rapidly proliferate and undergo somatic hypermutation and a light zone where B cells compete for interaction with T follicular helper cells, which enables them to undergo further differentiation [4]. Phenotypic transitions occurring during the GC reaction require B cells to undergo major reorganization of their three-dimensional (3D) genome architecture to coordinate specific transcription programs [5,6]. Most B-cell lymphomas are of GC B-cell origin, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma.
hIgDFc-Ig inhibits B cell function by regulating the BCR-Syk-Btk-NF-κB signalling pathway in mice with collagen-induced arthritis
2021, Pharmacological ResearchCitation Excerpt :Phosphorylation of these ITIM-containing receptors by Lyn leads to the recruitment of SHIP-1 and Src homology region 2 domain, both of which contain phosphatase 1 (SHP-1) that inhibits downstream BCR signalling [18]. The activation of BCR signalling affects the expression of downstream transcription factors, and maintenance of B cell function is dependent on the regulation of transcription factors [19,20]. E2A, IRF4, Pax5 and BLIMP-1 are important transcription factors, which play a role in controlling cell fate in B cell lines by promoting proliferation and differentiation [21,22].