The Transcriptional Regulation of Germinal Center Formation

Song, Shuang; Matthias, Patrick

doi:10.3389/fimmu.2018.02026

Cited by 50 publications

(141 citation statements)

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“…Interestingly, 61.5% of the changes between NBC and GCBC involved compartment activation (Figure 2C-D). As the germinal center reaction is known to be mediated by specific transcription factors (TFs) 42,43 and those may be involved in shaping the spatial organization of the genome 8,14,16 , we further explored the presence of TF binding motifs in the newly activated compartments. We identified significantly enriched motifs for MEF2 and POU families (Figure 2F and Supplementary Table 3) , which are essential TFs involved in germinal center formation 44–47 .…”

Section: Resultsmentioning

confidence: 99%

“…In this context, TFs have been described to act as the architects instructing structural changes in the genome 75 and a recent report has described that TFs are able to drive topological genome reorganizations even before detectable changes in gene expression 8 . A detailed analysis of regions that become exclusively active in GCBC as compared to any other B cell subpopulation under study revealed an enrichment in TF binding motifs of MEF2 and POU families, which have been described to play a key role in the germinal center formation 43 . In line with this important role of TFs in activating chromatin in GCBC, we also identified that…”

Section: Discussionmentioning

confidence: 97%

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Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Vilarrasa‐Blasi

Soler-Vila

Verdaguer-Dot

et al. 2019

Preprint

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Despite recent advances, the dynamics of genome architecture and chromatin function during human cell differentiation and its potential reorganization upon neoplastic transformation remains poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the dynamic changes in three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data reveals the presence of a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Vilarrasa‐Blasi

Soler-Vila

Verdaguer-Dot

et al. 2019

Preprint

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show abstract

“…This strategy is understandable, as it provides a framework for thinking about the cell-cell and molecular events responsible for the observed response. [21][22][23][24][25] Hence, we will provide a bird's eye view of these structures to set the stage for our discussion on the key events in extrafollicular responses and how they contrast with GCbased responses. for the response in question.…”

Section: Ba S Ic Elements Of the G Erminal Center Re Ac Ti Onmentioning

confidence: 99%

“…[18][19][20] Germinal centers have been reviewed by multiple writers and from numerous angles. [21][22][23][24][25] Hence, we will provide a bird's eye view of these structures to set the stage for our discussion on the key events in extrafollicular responses and how they contrast with GCbased responses. Very early in responses induced by proteinaceous antigens activated B and T cells congregate at boundaries between T cell rich regions in the spleen or lymph node and B-cell enriched follicles.…”

Section: Antibodies B Cells Cell Differentiation Germinal Centersmentioning

confidence: 99%

The continuing story of T‐cell independent antibodies

Allman

Wilmore

Gaudette

2019

Immunological Reviews

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Summary The purpose of this article is to review the role of extrafollicular and T‐cell independent antibody responses in humoral immunity. We consider two interrelated questions: (a) do T‐cell independent antibody responses dominated by IgM and/or IgA play unique functions in immunity and homeostasis; and (b) is it typical for these responses to result in lifelong protection? In addressing these questions, we consider the established advantages of T‐cell driven responses including the unique role played by germinal center reactions in these responses, and contrast the processes and outcomes of germinal center‐centric responses with germinal center‐ and T‐cell independent antibodies. We suggest that T‐independent and other extrafollicular responses contribute substantially to highly stable antibody repertoires in both the serum and the intestine, providing relatively constitutive humoral barriers with the collective dual function of protecting against invading pathogens and regulating the composition of non‐pathogenic microbial communities.

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“…Quantitative modelling of GCs : At the molecular level, the intracellular mechanisms associated with regulation of the B cells, T

and FDCs interactions implicates more than 100 transcription factors [ 16 ], most of which interact in highly regulated non-linear networks [ 17 ], making the precise quantitative modeling of GC reaction tremendously complex. As GCs are stochastic systems that display a high level of variability even within the same lymph node of the same individual [ 18 ], mathematical models have been widely used to deepen our understanding of the cellular and molecular processes characterising these complex dynamic systems [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts

Pélissier

Akrout

Jahn

et al. 2020

Cells

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Germinal centers (GCs) are specialized compartments within the secondary lymphoid organs where B cells proliferate, differentiate, and mutate their antibody genes in response to the presence of foreign antigens. Through the GC lifespan, interclonal competition between B cells leads to increased affinity of the B cell receptors for antigens accompanied by a loss of clonal diversity, although the mechanisms underlying clonal dynamics are not completely understood. We present here a multi-scale quantitative model of the GC reaction that integrates an intracellular component, accounting for the genetic events that shape B cell differentiation, and an extracellular stochastic component, which accounts for the random cellular interactions within the GC. In addition, B cell receptors are represented as sequences of nucleotides that mature and diversify through somatic hypermutations. We exploit extensive experimental characterizations of the GC dynamics to parameterize our model, and visualize affinity maturation by means of evolutionary phylogenetic trees. Our explicit modeling of B cell maturation enables us to characterise the evolutionary processes and competition at the heart of the GC dynamics, and explains the emergence of clonal dominance as a result of initially small stochastic advantages in the affinity to antigen. Interestingly, a subset of the GC undergoes massive expansion of higher-affinity B cell variants (clonal bursts), leading to a loss of clonal diversity at a significantly faster rate than in GCs that do not exhibit clonal dominance. Our work contributes towards an in silico vaccine design, and has implications for the better understanding of the mechanisms underlying autoimmune disease and GC-derived lymphomas.

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The Transcriptional Regulation of Germinal Center Formation

Cited by 50 publications

References 100 publications

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

The continuing story of T‐cell independent antibodies

Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts

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