Integrative transcriptome and chromatin landscape analysis reveals distinct epigenetic regulations in human memory B cells

Abstract Memory B cells (MBCs) are long-lived and produce high-affinity, generally, class-switched antibodies. Here, we use a multiparameter approach involving CD27 to segregate naïve B cells (NBC), IgD+ unswitched (unsw)MBCs and IgG+ or IgA+ class-switched (sw)MBCs from humans of different age, sex and race. Conserved antibody variable gene expression indicates that MBCs emerge through unbiased selection from NBCs. Integrative analyses of mRNAs, miRNAs, lncRNAs, chromatin accessibility and cis-regulatory elements uncover a core mRNA-ncRNA transcriptional signature shared by IgG+ and IgA+ swMBCs and distinct from NBCs, while unswMBCs display a transitional transcriptome. Some swMBC transcriptional signature loci are accessible but not expressed in NBCs. Profiling miRNAs reveals downregulated MIR181, and concomitantly upregulated MIR181 target genes such as RASSF6, TOX, TRERF1, TRPV3 and RORα, in swMBCs. Finally, lncRNAs differentially expressed in swMBCs cluster proximal to the IgH chain locus on chromosome 14. Our findings thus provide new insights into MBC transcriptional programs and epigenetic regulation, opening new investigative avenues on these critical cell elements in human health and disease.

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Chromatin accessibility and regulatory vocabulary across indicine cattle tissues

Genome Biology ◽

10.1186/s13059-021-02489-7 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Pâmela A. Alexandre ◽

Marina Naval-Sánchez ◽

Moira Menzies ◽

Loan T. Nguyen ◽

Laercio R. Porto-Neto ◽

...

Keyword(s):

Motif Discovery ◽

Target Genes ◽

Developmental Stages ◽

Bos Taurus ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Model Organisms ◽

Open Chromatin ◽

Health And Disease ◽

Collaborative Efforts

Abstract Background Spatiotemporal changes in the chromatin accessibility landscape are essential to cell differentiation, development, health, and disease. The quest of identifying regulatory elements in open chromatin regions across different tissues and developmental stages is led by large international collaborative efforts mostly focusing on model organisms, such as ENCODE. Recently, the Functional Annotation of Animal Genomes (FAANG) has been established to unravel the regulatory elements in non-model organisms, including cattle. Now, we can transition from prediction to validation by experimentally identifying the regulatory elements in tropical indicine cattle. The identification of regulatory elements, their annotation and comparison with the taurine counterpart, holds high promise to link regulatory regions to adaptability traits and improve animal productivity and welfare. Results We generate open chromatin profiles for liver, muscle, and hypothalamus of indicine cattle through ATAC-seq. Using robust methods for motif discovery, motif enrichment and transcription factor binding sites, we identify potential master regulators of the epigenomic profile in these three tissues, namely HNF4, MEF2, and SOX factors, respectively. Integration with transcriptomic data allows us to confirm some of their target genes. Finally, by comparing our results with Bos taurus data we identify potential indicine-specific open chromatin regions and overlaps with indicine selective sweeps. Conclusions Our findings provide insights into the identification and analysis of regulatory elements in non-model organisms, the evolution of regulatory elements within two cattle subspecies as well as having an immediate impact on the animal genetics community in particular for a relevant productive species such as tropical cattle.

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Understanding and making use of human memory B cells

Immunological Reviews ◽

10.1111/j.0105-2896.2006.00403.x ◽

2006 ◽

Vol 211 (1) ◽

pp. 303-309 ◽

Cited By ~ 115

Author(s):

Antonio Lanzavecchia ◽

Nadia Bernasconi ◽

Elisabetta Traggiai ◽

Claudia R. Ruprecht ◽

Davide Corti ◽

...

Keyword(s):

B Cells ◽

Human Memory ◽

Memory B Cells

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ASC proneural transcription factors mediate the timely initiation of the neural program during neuroectodermal to neuroblast transition ensuring progeny fidelity

10.1101/2021.11.02.466869 ◽

2021 ◽

Author(s):

Vasiliki Theodorou ◽

Aikaterini Stefanaki ◽

Minas Drakos ◽

Dafne Triantafyllou ◽

Christos Delidakis

Keyword(s):

Transcription Factors ◽

Target Genes ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Cis Elements ◽

Enhancer Activity ◽

Timely Initiation ◽

Chromatin Dynamics ◽

Neural Fate ◽

Neural Specification

Background: ASC/ASCL proneural transcription factors are oncogenic and exhibit impressive reprogramming and pioneer activities. In both Drosophila and mammals, these factors are central in the early specification of the neural fate, where they act in opposition to Notch signalling. However, the role of ASC on the chromatin during CNS neural stem cells birth remains elusive. Results: We investigated the chromatin changes accompanying neural commitment using an integrative genetics and genomics methodology. We found that ASC factors bind equally strongly to two distinct classes of cis-regulatory elements: open regions remodeled earlier during maternal to zygotic transition by Zelda and Zelda-independent, less accessible regions. Both classes cis-elements exhibit enhanced chromatin accessibility during neural specification and correlate with transcriptional regulation of genes involved in many biological processes necessary for neuroblast function. We identified an ASC-Notch regulated TF network that most likely act as the prime regulators of neuroblast function. Using a cohort of ASC target genes, we report that ASC null neuroblasts are defectively specified, remaining initially stalled, lacking expression of many proneural targets and unable to divide. When they eventually start proliferating, they produce compromised progeny. Generation of lacZ reporter lines driven by proneural-bound elements display enhancer activity within neuroblasts and proneural dependency. Therefore, the partial neuroblast identity seen in the absence of ASC genes is driven by other, proneural-independent, cis-elements. Neuroblast impairment and the late differentiation defects of ASC mutants are corrected by ectodermal induction of individual ASC genes but not by individual members of the TF network downstream of ASC. However, in wild type embryos induction of individual members of this network induces CNS hyperplasia, suggesting that they synergize with the activating function of ASC to establish the chromatin dynamics that promote neural specification. Conclusion: ASC factors bind a large number of enhancers to orchestrate the timely activation of the neural chromatin program during neuroectodermal to neuroblast transition. This early chromatin remodeling is crucial for both neuroblast homeostasis as well as future progeny fidelity.

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BAFF selectively enhances the survival of plasmablasts generated from human memory B cells

Journal of Clinical Investigation ◽

10.1172/jci18025e1 ◽

2004 ◽

Vol 113 (7) ◽

pp. 1069-1069

Author(s):

Danielle T. Avery ◽

Susan L. Kalled ◽

Julia I. Ellyard ◽

Christine Ambrose ◽

Sarah A. Bixler ◽

...

Keyword(s):

B Cells ◽

Human Memory ◽

Memory B Cells

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Complexity of the human memory B-cell compartment is determined by the versatility of clonal diversification in germinal centers

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1511270112 ◽

2015 ◽

Vol 112 (38) ◽

pp. E5281-E5289 ◽

Cited By ~ 29

Author(s):

Bettina Budeus ◽

Stefanie Schweigle de Reynoso ◽

Martina Przekopowitz ◽

Daniel Hoffmann ◽

Marc Seifert ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Clone ◽

Human Memory ◽

Memory B Cells ◽

Sequencing Analysis ◽

Cell Compartment ◽

Memory B Cell ◽

Cell Clones ◽

B Cell Subsets

Our knowledge about the clonal composition and intraclonal diversity of the human memory B-cell compartment and the relationship between memory B-cell subsets is still limited, although these are central issues for our understanding of adaptive immunity. We performed a deep sequencing analysis of rearranged immunoglobulin (Ig) heavy chain genes from biological replicates, covering more than 100,000 memory B lymphocytes from two healthy adults. We reveal a highly similar B-cell receptor repertoire among the four main human IgM+ and IgG+ memory B-cell subsets. Strikingly, in both donors, 45% of sequences could be assigned to expanded clones, demonstrating that the human memory B-cell compartment is characterized by many, often very large, B-cell clones. Twenty percent of the clones consisted of class switched and IgM+(IgD+) members, a feature that correlated significantly with clone size. Hence, we provide strong evidence that the vast majority of Ig mutated B cells—including IgM+IgD+CD27+ B cells—are post-germinal center (GC) memory B cells. Clone members showed high intraclonal sequence diversity and high intraclonal versatility in Ig class and IgG subclass composition, with particular patterns of memory B-cell clone generation in GC reactions. In conclusion, GC produce amazingly large, complex, and diverse memory B-cell clones, equipping the human immune system with a versatile and highly diverse compartment of IgM+(IgD+) and class-switched memory B cells.

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Modeling gene regulation from paired expression and chromatin accessibility data

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1704553114 ◽

2017 ◽

Vol 114 (25) ◽

pp. E4914-E4923 ◽

Cited By ~ 76

Author(s):

Zhana Duren ◽

Xi Chen ◽

Rui Jiang ◽

Yong Wang ◽

Wing Hung Wong

Keyword(s):

Gene Expression ◽

Target Genes ◽

Transcriptional Regulatory Network ◽

Joint Modeling ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Exciting Opportunity ◽

Transcriptional Regulatory ◽

Dna Elements ◽

Context Specific

The rapid increase of genome-wide datasets on gene expression, chromatin states, and transcription factor (TF) binding locations offers an exciting opportunity to interpret the information encoded in genomes and epigenomes. This task can be challenging as it requires joint modeling of context-specific activation of cis-regulatory elements (REs) and the effects on transcription of associated regulatory factors. To meet this challenge, we propose a statistical approach based on paired expression and chromatin accessibility (PECA) data across diverse cellular contexts. In our approach, we model (i) the localization to REs of chromatin regulators (CRs) based on their interaction with sequence-specific TFs, (ii) the activation of REs due to CRs that are localized to them, and (iii) the effect of TFs bound to activated REs on the transcription of target genes (TGs). The transcriptional regulatory network inferred by PECA provides a detailed view of how trans- and cis-regulatory elements work together to affect gene expression in a context-specific manner. We illustrate the feasibility of this approach by analyzing paired expression and accessibility data from the mouse Encyclopedia of DNA Elements (ENCODE) and explore various applications of the resulting model.

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A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells

Blood ◽

10.1182/blood-2002-11-3569 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4500-4504 ◽

Cited By ~ 463

Author(s):

Nadia L. Bernasconi ◽

Nobuyuki Onai ◽

Antonio Lanzavecchia

Keyword(s):

B Cells ◽

B Cell ◽

Constitutive Expression ◽

Human Memory ◽

Cell Receptor ◽

Primary Response ◽

Memory B Cells ◽

Toll Like Receptors ◽

Polyclonal Activation ◽

B Cell Subsets

Abstract Toll-like receptors (TLRs) are pattern recognition receptors that trigger innate immunity. In this study we investigated the expression of 10 TLRs in human naive and memory B-cell subsets. We report that in human naive B cells most TLRs are expressed at low to undetectable levels, but the expression of TLR9 and TLR10 is rapidly induced following B-cell-receptor (BCR) triggering. In contrast, memory B cells express several TLRs at constitutively high levels. The differential expression of TLR9 correlates with responsiveness to its agonist, CpG DNA. Thus, human memory B cells proliferate and differentiate to immunoglobulin (Ig)–secreting cells in response to CpG, while naive B do so only if simultaneously triggered through the BCR. The BCR-induced expression of TLRs in human naive B cells prevents polyclonal activation in a primary response, because it restricts stimulation to antigen-specific B cells. In contrast, the constitutive expression of TLRs in memory B cells allows polyclonal activation of the entire memory pool. Thus, in human B cells TLRs are downstream of BCR and play a role both in the primary response and in the memory phase.

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Resting Human Memory B Cells Are Intrinsically Programmed for Enhanced Survival and Responsiveness to Diverse Stimuli Compared to Naive B Cells

The Journal of Immunology ◽

10.4049/jimmunol.182.2.890 ◽

2009 ◽

Vol 182 (2) ◽

pp. 890-901 ◽

Cited By ~ 154

Author(s):

Kim L. Good ◽

Danielle T. Avery ◽

Stuart G. Tangye

Keyword(s):

B Cells ◽

Human Memory ◽

Memory B Cells

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Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways

Blood ◽

10.1182/blood-2011-04-345579 ◽

2011 ◽

Vol 118 (8) ◽

pp. 2150-2158 ◽

Cited By ~ 217

Author(s):

Magdalena A. Berkowska ◽

Gertjan J. A. Driessen ◽

Vasilis Bikos ◽

Christina Grosserichter-Wagener ◽

Kostas Stamatopoulos ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Somatic Hypermutation ◽

Phenotypic Diversity ◽

Human Memory ◽

Memory B Cells ◽

Memory B Cell ◽

Effector Cells ◽

B Cell Subsets

Abstract Multiple distinct memory B-cell subsets have been identified in humans, but it remains unclear how their phenotypic diversity corresponds to the type of responses from which they originate. Especially, the contribution of germinal center-independent responses in humans remains controversial. We defined 6 memory B-cell subsets based on their antigen-experienced phenotype and differential expression of CD27 and IgH isotypes. Molecular characterization of their replication history, Ig somatic hypermutation, and class-switch profiles demonstrated their origin from 3 different pathways. CD27−IgG+ and CD27+IgM+ B cells are derived from primary germinal center reactions, and CD27+IgA+ and CD27+IgG+ B cells are from consecutive germinal center responses (pathway 1). In contrast, natural effector and CD27−IgA+ memory B cells have limited proliferation and are also present in CD40L-deficient patients, reflecting a germinal center-independent origin. Natural effector cells at least in part originate from systemic responses in the splenic marginal zone (pathway 2). CD27−IgA+ cells share low replication history and dominant Igλ and IgA2 use with gut lamina propria IgA+ B cells, suggesting their common origin from local germinal center-independent responses (pathway 3). Our findings shed light on human germinal center-dependent and -independent B-cell memory formation and provide new opportunities to study these processes in immunologic diseases.

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