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Journal ArticleDOI: 10.1182/BLOOD.2020005083

Plasmablasts derive from CD23– activated B cells after the extinction of IL-4/STAT6 signaling and IRF4 induction

04 Mar 2021-Blood (American Society of Hematology)-Vol. 137, Iss: 9, pp 1166-1180
Abstract: The terminal differentiation of B cells into antibody-secreting cells (ASCs) is a critical component of adaptive immune responses. However, it is a very sensitive process, and dysfunctions lead to a variety of lymphoproliferative neoplasias including germinal center–derived lymphomas. To better characterize the late genomic events that drive the ASC differentiation of human primary naive B cells, we used our in vitro differentiation system and a combination of RNA sequencing and Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC sequencing). We discovered 2 mechanisms that drive human terminal B-cell differentiation. First, after an initial response to interleukin-4 (IL-4), cells that were committed to an ASC fate downregulated the CD23 marker and IL-4 signaling, whereas cells that maintained IL-4 signaling did not differentiate. Second, human CD23– cells also increased IRF4 protein to levels required for ASC differentiation, but they did that independently of the ubiquitin-mediated degradation process previously described in mice. Finally, we showed that CD23– cells carried the imprint of their previous activated B-cell status, were precursors of plasmablasts, and had a phenotype similar to that of in vivo preplasmablasts. Altogether, our results provide an unprecedented genomic characterization of the fate decision between activated B cells and plasmablasts, which provides new insights into the pathological mechanisms that drive lymphoma biology.

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Topics: Interleukin 4 (55%), Naive B cell (54%), CD23 (53%) ... read more
Citations
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7 results found


Journal ArticleDOI: 10.1016/J.PRP.2021.153477
Abstract: Signal Transducer and Activator of Transcription 6 (STAT6), belonging to a family of seven similar members is primarily stimulated by interleukin(IL)-4 and IL-13, and acts as a T helper type 2 (Th2)-inducing factor. Thus, it is implicated in the pathophysiology of various allergic conditions, such as asthma, atopic dermatitis, eosinophilic esophagitis and food allergies, but also in tumor microenvironment regulation. Furthermore, certain forms of lymphomas, notably the Hodgkin lymphoma group, the primary mediastinal and primary central nervous system lymphoma, as well as some follicular and T cell lymphomas are associated with dysregulation of the STAT6 pathway. STAT6 immunohistochemical expression also serves as a surrogate marker in the diagnosis of solitary fibrous tumor, despite not directly responsible for the tumorigenic effect. These pathophysiological implications of the STAT6 pathway, its diagnostic or prognostic role in pathology, as well its immunohistochemical detection with different antibodies will be discussed in this review.

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Topics: Primary central nervous system lymphoma (55%), Tumor microenvironment (53%), Lymphoma (52%) ... read more

5 Citations


Open accessProceedings Article
Joshua D. Welch1, Ziqing Liu1, Li Wang2, Junjie Lu3  +5 moreInstitutions (4)
01 Jan 2016-
Abstract: Single cell experiments provide an unprecedented opportunity to reconstruct a sequence of changes in a biological process from individual “snapshots” of cells. However, nonlinear gene expression changes, genes unrelated to the process, and the possibility of branching trajectories make this a challenging problem. We develop SLICER (Selective Locally Linear Inference of Cellular Expression Relationships) to address these challenges. SLICER can infer highly nonlinear trajectories, select genes without prior knowledge of the process, and automatically determine the location and number of branches and loops. SLICER recovers the ordering of points along simulated trajectories more accurately than existing methods. We demonstrate the effectiveness of SLICER on previously published data from mouse lung cells and neural stem cells.

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4 Citations


Open accessJournal ArticleDOI: 10.2147/PGPM.S309166
Jie Wang1, Jie Wang2, Yun Wu1, Nazim Uddin3  +3 moreInstitutions (3)
Abstract: Introduction Essential thrombocytosis (ET) is a group of myeloproliferative neoplasms characterized by abnormal proliferation of platelet and megakaryocytes. Research on potential key genes and novel regulatory markers in essential thrombocythemia (ET) is still limited. Methods Downloading array profiles from the Gene Expression Omnibus database, we identified the differentially expressed genes (DEGs) through comprehensive bioinformatic analysis. GO, and REACTOME pathway enrichment analysis was used to predict the potential functions of DEGs. Besides, constructing a protein-protein interaction (PPI) network through the STRING database, we validated the expression level of hub genes in an independent cohort of ET, and the transcription factors (TFs) were detected in the regulatory networks of TFs and DEGs. And the candidate drugs that are targeting hub genes were identified using the DGIdb database. Results We identified 63 overlap DEGs that included 21 common up-regulated and 42 common down-regulated genes from two datasets. Functional enrichment analysis shows that the DEGs are mainly enriched in the immune system and inflammatory processes. Through PPI network analysis, ACTB, PTPRC, ACTR2, FYB, STAT1, ETS1, IL7R, IKZF1, FGL2, and CTSS were selected as hub genes. Interestingly, we found that the dysregulated hub genes are also aberrantly expressed in a bone marrow cohort of ET. Moreover, we found that the expression of CTSS, FGL2, IKZF1, STAT1, FYB, ACTR2, PTPRC, and ACTB genes were significantly under-expressed in ET (P<0.05), which is consistent with our bioinformatics analysis. The ROC curve analysis also shows that these hub genes have good diagnostic value. Besides, we identified 4 TFs (SPI1, IRF4, SRF, and AR) as master transcriptional regulators that were associated with regulating the DEGs in ET. Cyclophosphamide, prednisone, fluorouracil, ruxolitinib, and lenalidomide were predicted as potential candidate drugs for the treatment of ET. Discussion These dysregulated genes and predicted key regulators had a significant relationship with the occurrence of ET with affecting the immune system and inflammation of the processes. Some of the immunomodulatory drugs have potential value by targeting ACTB, PTPRC, IL7R, and IKZF1 genes in the treatment of ET.

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Topics: PTPRC (53%)

2 Citations


Journal ArticleDOI: 10.1016/J.IMMUNI.2021.08.028
Lihui Duan1, Dan Liu1, Hsin Chen1, Michelle A. Mintz1  +6 moreInstitutions (2)
12 Oct 2021-Immunity
Abstract: B cells within germinal centers (GCs) enter cycles of antibody affinity maturation or exit the GC as memory cells or plasma cells. Here, we examined the contribution of interleukin (IL)-4 on B cell fate decisions in the GC. Single-cell RNA-sequencing identified a subset of light zone GC B cells expressing high IL-4 receptor-a (IL4Ra) and CD23 and lacking a Myc-associated signature. These cells could differentiate into pre-memory cells. B cell-specific deletion of IL4Ra or STAT6 favored the pre-memory cell trajectory, and provision of exogenous IL-4 in a wild-type context reduced pre-memory cell frequencies. IL-4 acted during antigen-specific interactions but also influenced bystander cells. Deletion of IL4Ra from follicular dendritic cells (FDCs) increased the availability of IL-4 in the GC, impaired the selection of affinity-matured B cells, and reduced memory cell generation. We propose that GC FDCs establish a niche that limits bystander IL-4 activity, focusing IL-4 action on B cells undergoing selection and enhancing memory cell differentiation.

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Topics: Memory B cell (69%), Follicular dendritic cells (66%), Germinal center (66%) ... read more

Journal ArticleDOI: 10.1016/J.BBCAN.2021.188632
Sijia Gu1, Ling Qian1, Yalei Zhang1, Kun Chen1  +3 moreInstitutions (1)
Abstract: Immunotherapy for cancer has provided new treatment approaches for malignant tumors, but there are low rates of response and high rates of resistance. The most recent sequencing method which is called single-cell RNA sequencing(scRNA-seq) determines the transcriptome at the single cell level, which allows high-resolution dynamic monitoring of the tumor microenvironment (TME) during immunotherapy. As an important part of humoral immunity, tumor-infiltrated B cells have been reported to have distinct functions in anti-tumor immunity, which are characterized by their RNA transcriptome, membrane surface receptors, and immunoglobulin secretion, suggesting great immunotherapeutic effects. On the basis of the important roles of B cells in immunotherapy reported in recent publications, we discuss the tumor-infiltrated B cells' subpopulations, differentiation trajectory, and interactions with other cells in the TME in this review, hoping to illustrate its significance in potential clinical application as biomarkers and therapeutic targets.

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Topics: Cancer immunotherapy (57%), Immunoglobulin secretion (56%), Transcriptome (55%) ... read more

References
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71 results found


Open accessJournal ArticleDOI: 10.1186/S13059-014-0550-8
05 Dec 2014-Genome Biology
Abstract: In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html .

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Topics: MRNA Sequencing (54%), Integrator complex (51%), Count data (50%) ... read more

29,675 Citations


Open accessJournal ArticleDOI: 10.1038/NMETH.1923
01 Apr 2012-Nature Methods
Abstract: As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.

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27,973 Citations


Open accessJournal ArticleDOI: 10.1186/GB-2009-10-3-R25
04 Mar 2009-Genome Biology
Abstract: Bowtie is an ultrafast, memory-efficient alignment program for aligning short DNA sequence reads to large genomes. For the human genome, Burrows-Wheeler indexing allows Bowtie to align more than 25 million reads per CPU hour with a memory footprint of approximately 1.3 gigabytes. Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches. Multiple processor cores can be used simultaneously to achieve even greater alignment speeds. Bowtie is open source http://bowtie.cbcb.umd.edu.

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Topics: Hybrid genome assembly (51%)

18,079 Citations


Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTU638
15 Jan 2015-Bioinformatics
Abstract: Motivation: A large choice of tools exists for many standard tasks in the analysis of high-throughput sequencing (HTS) data. However, once a project deviates from standard workflows, custom scripts are needed. Results: We present HTSeq, a Python library to facilitate the rapid development of such scripts. HTSeq offers parsers for many common data formats in HTS projects, as well as classes to represent data, such as genomic coordinates, sequences, sequencing reads, alignments, gene model information and variant calls, and provides data structures that allow for querying via genomic coordinates. We also present htseq-count, a tool developed with HTSeq that preprocesses RNA-Seq data for differential expression analysis by counting the overlap of reads with genes. Availability and implementation: HTSeq is released as an opensource software under the GNU General Public Licence and available from http://www-huber.embl.de/HTSeq or from the Python Package Index at https://pypi.python.org/pypi/HTSeq. Contact: sanders@fs.tum.de

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11,833 Citations


Open accessJournal ArticleDOI: 10.1016/J.MOLCEL.2010.05.004
28 May 2010-Molecular Cell
Abstract: Genome-scale studies have revealed extensive, cell type-specific colocalization of transcription factors, but the mechanisms underlying this phenomenon remain poorly understood. Here, we demonstrate in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions. PU.1 binding initiates nucleosome remodeling, followed by H3K4 monomethylation at large numbers of genomic regions associated with both broadly and specifically expressed genes. These locations serve as beacons for additional factors, exemplified by liver X receptors, which drive both cell-specific gene expression and signal-dependent responses. Together with analyses of transcription factor binding and H3K4me1 patterns in other cell types, these studies suggest that simple combinations of lineage-determining transcription factors can specify the genomic sites ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs.

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Topics: Pioneer factor (61%), General transcription factor (61%), Super-enhancer (61%) ... read more

7,287 Citations