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B cell differentiation into germinal center and antibody-secreting cells depends on SMARCA5-mediated chromatin remodeling[CUT & RUN]

ABSTRACT: The establishment of long-lasting immunity against pathogens is facilitated by the germinal center (GC) reaction, during which B cells increase their antibody affinity, and differentiate into antibody-secreting cells (ASC) and memory cells. These events involve modifications in chromatin packaging that orchestrate the profound restructuring of gene expression networks that determine cell fate. While several chromatin remodelers were implicated in lymphocyte functions, less is known about SMARCA5. Here, by using ribosomal pull-down for analyzing translated genes in GC B cells, coupled with functional experiments in mice, we identified SMARACA5 as a key chromatin remodeler in B cells. While the naive B cell compartment and early B cell activation remained unaffected following conditional depletion of Smarca5, immunoglobulin class switching, GC formation and ASC differentiation were impaired. Single-cell multi-omic sequencing analyses revealed that SMARCA5 is crucial for facilitating the transcriptional modifications and genomic accessibility of genes that support B cell differentiation. These findings offer novel insights into SMARCA5, which can be targeted in lymphoma patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE260881 | GEO | 2024/09/01

REPOSITORIES: GEO

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B cell differentiation into germinal center and antibody-secreting cells depends on SMARCA5-mediated chromatin remodeling[Ribotag]

Project description:The establishment of long-lasting immunity against pathogens is facilitated by the germinal center (GC) reaction, during which B cells increase their antibody affinity, and differentiate into antibody-secreting cells (ASC) and memory cells. These events involve modifications in chromatin packaging that orchestrate the profound restructuring of gene expression networks that determine cell fate. While several chromatin remodelers were implicated in lymphocyte functions, less is known about SMARCA5. Here, by using ribosomal pull-down for analyzing translated genes in GC B cells, coupled with functional experiments in mice, we identified SMARACA5 as a key chromatin remodeler in B cells. While the naive B cell compartment and early B cell activation remained unaffected following conditional depletion of Smarca5, immunoglobulin class switching, GC formation and ASC differentiation were impaired. Single-cell multi-omic sequencing analyses revealed that SMARCA5 is crucial for facilitating the transcriptional modifications and genomic accessibility of genes that support B cell differentiation. These findings offer novel insights into SMARCA5, which can be targeted in lymphoma patients.

2024-09-01 | GSE270216 | GEO

B cell differentiation into germinal center and antibody-secreting cells depends on SMARCA5-mediated chromatin remodeling[RNA-Seq]

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B cell differentiation into germinal center and antibody-secreting cells depends on SMARCA5-mediated chromatin remodeling[scMultiome - RNA + ATAC]

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Human SMARCA5 interactome in transgenic SMARCA5 mouse model

Project description:We hypothesize that the ISWI ATPase Smarca5 plays a role in hematopoietic stem cell development via its interaction partners, and to study the role, we used a mouse model with transgenic expression of SMARCA5 coupled with mass spectrometry analysis. The study uses transgenic SMARCA5 mouse model with conditional hypomorphic allele (lower expression on protein level compared to controls) incorporated into Rosa26 locus, transgenic allele uses endogenous Rosa26 promoter. The transgenic human SMARCA5 protein has a FLAG tag at its C-terminus, which allows specific immunoprecipitation and also differentiation from the endogenous protein (human and mouse SMARCA5 are almost identical at the protein level). To ensure the highest possible expression of the transgenic allele, we used a model that also had one endogenous Smarca5 allele deleted. Various organs (thymus, spleen, brain, kidney, liver, testes, muscle, fetal liver) were isolated from transgenic mice, lysed and then immunoprecipitated using anti-FLAG antibody. The immunoprecipitates were then analyzed using mass spectrometry to determine SMARCA5 interactomes in various tissues. Transgenic human SMARCA5 was confirmed to form all the expected complexes and capable of replacing the functions of the mouse protein. For details, see the publication of Turkova et al. 2024 in Communications Biology.

2024-06-22 | PXD049034 | Pride

Extrafollicular IgD+ B cells Generate IgE Antibody Secreting Cells in the Nasal Mucosa

Project description:Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using VH next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class-switch.

2021-05-13 | GSE174349 | GEO

Characterization of gene expression in antibody secreting cells

Project description:The CD19 positive antibody secreting cells (ASC) in both bone marrow (BM) have the capacity to provide immune memory in addition to cells traditionally considered long-lived, the CD19-negative BM ASC. We performed flow cytometry (FCM) immunophenotyping, fluorescence-activated cell sorting (FACS) for cell subset isolation, ELISpot assays detecting the isotype of antibody secretion as well as antibodies against vaccine derived antigens, and comparative gene expression analyses of CD19- ASC, CD19+ ASC, CD20- B cells, and CD20+ B cells from BM. The findings may aid in the understanding of the differential cell subsets created through vaccination and lead to improved vaccine strategies and production. FACS sorted tissue B cells and antibody secreting cell subset gene expression.

2018-12-03 | GSE107683 | GEO

ATAC-seq time course analysis of in vitro differentiated antibody-secreting cells

Project description:We examined the chromatin accessibility changes that occur as antibody-secreting cells (ASC) differentiate and mature using an in vitro culture system. ASC were profiled directly post isolation and at time points weekly out to 14 days in culture. These data reveal how the long-lived ASC accessible chromatin matures over time.

2022-01-14 | GSE193644 | GEO

Mouse P0 cerebellum: Smarca5 conditional KO mice (cKO) versus wild type controls

Project description:Gene expression profiling of mouse cerebellum in which the experimental strain conditionally lack the Smarca5 gene that encodes for the catalytic subunit of multiple chromatin remodeling complexes. Deletion of Smarca5 was restricted to those cells expressing Cre-recombinase driven by the Nestin promoter. Comparison of gene expression in P0 cerebella of Smarca5 cKO mice versus wild type controls. Three samples of each strain were used in a total of 4 replicates.

2014-04-30 | E-GEOD-42369 | biostudies-arrayexpress

Mouse P10 cerebellum: Smarca5 conditional KO mice (cKO) versus wild type controls

Project description:Gene expression profiling of mouse cerebellum in which the experimental strain conditionally lack the Smarca5 gene that encodes for the catalytic subunit of multiple chromatin remodeling complexes. Deletion of Smarca5 was restricted to those cells expressing Cre-recombinase driven by the Nestin promoter. Comparison of gene expression in P10 cerebella of Smarca5 cKO mice versus wild type controls. Three samples of each strain were used in a total of 3 replicates.

2014-04-30 | E-GEOD-42370 | biostudies-arrayexpress

Single-cell analysis reveals dynamics of human B cell differentiation and identifies novel B and antibody-secreting cell intermediates

Project description:Differentiation of B cells into antibody-secreting cells (ASCs) is a key process to generate protective humoral immunity. A detailed understanding of the cues controlling ASC differentiation is important to devise strategies to modulate antibody formation. Here, we dissected differentiation trajectories of human naive B cells into ASCs using single-cell RNA sequencing. By comparing transcriptomes of B cells at different stages of differentiation from an in vitro model with ex vivo B cells and ASCs, we uncovered a novel pre-ASC population present ex vivo in lymphoid tissues. For the first time, a germinal-center-like population is identified in vitro from human naive B cells and possibly progresses into a memory B cell population through an alternative route of differentiation, thus recapitulating in vivo human GC reactions. Our work allows further detailed characterization of human B cell differentiation into ASCs or memory B cells in both healthy and diseased conditions.

2022-09-27 | GSE214265 | GEO

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