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Defining AP4- and MYC-regulated gene expression programs in germinal center B cells during cyclic re-entry

ABSTRACT: B cells diversify and affinity-mature their antigen receptor repertoire in germinal centers (GC). GC B cells receive help signals during transient interaction with T cells, yet it remains unknown how these transient T-B interactions sustain the subsequent proliferative program of selected B cells. Here we show that the transcription factor AP4 is required for sustained GC B cell proliferation and subsequent establishment of a diverse and protective antibody repertoire. AP4 is induced by c-MYC during the T-B interactions and maintained by T cell-derived IL-21. B cell-specific deletion of AP4 resulted in reduced GC sizes and somatic hypermutation and a failure to control chronic viral infection. These results indicate that AP4 integrates T cell-mediated selection and sustained expansion of GC B cells for humoral immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE80669 | GEO | 2016/08/23

SECONDARY ACCESSION(S): PRJNA319639

REPOSITORIES: GEO

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Defining AP4- and MYC-regulated gene expression programs in germinal center B cells during cyclic re-entry

Project description:B cells diversify and affinity-mature their antigen receptor repertoire in germinal centers (GC). GC B cells receive help signals during transient interaction with T cells, yet it remains unknown how these transient T-B interactions sustain the subsequent proliferative program of selected B cells. Here we show that the transcription factor AP4 is required for sustained GC B cell proliferation and subsequent establishment of a diverse and protective antibody repertoire. AP4 is induced by c-MYC during the T-B interactions and maintained by T cell-derived IL-21. B cell-specific deletion of AP4 resulted in reduced GC sizes and somatic hypermutation and a failure to control chronic viral infection. These results indicate that AP4 integrates T cell-mediated selection and sustained expansion of GC B cells for humoral immunity. Splenic B cells activated with anti-IgM and CD40L in vitro and germinal center B cells sorted from C57BL/6 mice eight days after immunization with sheep red blood cells (SRBCs) were obtained and genome-wide occupancy of c-MYC, AP4 and active histone marks was profiled by chromatin immunoprecipitation and high-throughput sequencing. Gene expression in MYCâAP4â LZ, MYC+AP4+ LZ, AP4+ DZ, and APâ DZ GC B cells from SRBC-immunized AP4-mCherry / c-MYC-GFP dual reporter mice was profiled by RNA-seq.

2016-08-23 | E-GEOD-80669 | biostudies-arrayexpress

Genome-wide mapping of Myc, AP4, and phosphorylated RNA polymerase II binding in activated CD8 T cells by ChIP sequencing

Project description:The trasncription factor cMyc is an essential transcription factor that establishes a metabolically active and proliferative state in T cells after antigen priming. However, its expression is transient. To date, it remains unknown how T cell activation is maintained after cMyc down-regulation. Here, we identify AP4, encoded by the gene Tfap4, as the transcription factor that is induced by cMyc and sustains activation of antigen-specific CD8+ T cells. Despite normal priming, Tfap4–/– CD8+ T cells fail to continue transcription of a broad range of cMyc gene targets necessary for sustained proliferation. Genome-wide analysis suggests that many activation-induced metabolic genes are shared targets of cMyc and AP4. Thus, AP4 maintains Myc-initiated cellular activation programs in CD8+ T cells to control microbial infections. Naive CD8+ T cells from C57BL6 mice were activated with anti-CD3 and anti-CD28 stimulation in vitro for two days and genome-wide occupancy of Myc, AP4 and Ser2 or Ser5 phipsphorylated RNA polymerase II was profiled by chromatin immunoprecipitation and high-throughput sequencing.

2014-07-13 | E-GEOD-58075 | biostudies-arrayexpress

Genome-wide mapping of Myc, AP4, and phosphorylated RNA polymerase II binding in activated CD8 T cells by ChIP sequencing

2014-07-13 | GSE58075 | GEO

Defining AP4-regulated gene expression programs in pro/pre-B cells overexpressing c-MYC

Project description:A hallmark feature of adaptive immune cells is their capacity for rapid cell proliferation required for producing and expanding cells with a diverse repertoire of antigen receptor and amplification of antigen-specific receptors. While proliferation is beneficial for host protection from infection and cancers, it inevitably elevates the risk of oncogenic transformation. Developing lymphocytes, as well as B cells in the germinal center (GC), are considered tumor-prone due to additional genomic insults from physiological antigen receptor gene rearrangement and editing. However, oncogenic transformation of lymphocytes is relatively rare, perhaps owing to an intrinsic, tumor-suppressive program. Here, we show that c-MYC not only facilitates rapid cell proliferation but, unexpectedly, also engages a counteracting tumor suppressive program through its downstream transcription factor, AP4. Haploinsufficiency for AP4 dramatically accelerates MYC-driven tumorigenesis in a B cell-intrinsic manner. At a mechanistic level, AP4 suppresses Erg, which is required for B cell development but also oncogenic, in MYC+ developing B cells, and thus AP4 restricts simultaneous expression of multiple oncogenic factors during B cell development. Thus, c-MYC has dual action that permit proliferative expansion of B cell precursors, while concurrently safeguarding against their transformation via engagement of an AP4-dependent, tumor-suppressive program.

2021-06-19 | GSE133514 | GEO

ChIP-seq of AP4 binding in human colorectal cancer cells DLD-1.

Project description:In order to comprehensively identify genes directly regulated by AP4, a genome-wide chromatin-immunoprecipitation analysis (ChIP) followed by next generation sequencing (ChIP-seq) was performed after activation of a conditional AP4 allele in DLD-1 cells.

2013-05-31 | GSE46935 | GEO

Gene expression analysis of cMyc-deficient CD8 T cells retrovirally overexpressing cMyc or AP4

2014-07-13 | GSE58079 | GEO

ChIP-seq of AP4 binding in human colorectal cancer cells DLD-1.

2013-05-31 | E-GEOD-46935 | biostudies-arrayexpress

Altered expression of genes in AP4 knockdown and overexpression

Project description:The transcription factor AP4/TFAP4/AP-4 is a ubiquitously expressed basic helix-loop-helix leucine-zipper (bHLH-LZ) transcription factor, which forms homodimer that binds to the consensus E-box motif 5-CAGCTG-3. Prostatic adenocarcinoma (PAC), also known as prostate cancer, is the second most common malignancy of men with 914,000 new cases and approximately 258,000 deaths worldwide in 2008. The goal of this study is to identify the target genes of AP4 in prostate cancer. Our results demonstrated that the genes regulated by AP4 are involved in a variety of biological functions, such as proliferation and invasion. We used microarrays to detail the different expression of genes in AP4 knockdown and overexpression and identified distinct classes of up-regulated genes during this process.

2016-06-09 | GSE83140 | GEO

AP4 regulates stem and Paneth cell homeostasis and promotes adenoma initiation in the intestine (adenoma)

Project description:AP4 is frequently expressed in primary CRCs. However, the in vivo relevance of AP4 for development of intestinal tumor formation has not been analyzed by genetic approaches. ApcMin/+ mice with deletion of AP4 were generated and analyzed. The mRNA expression profiles of intestinal adenomas with and without functional AP4 were compared.

2018-12-25 | GSE99437 | GEO

Gene expression analysis of cMyc-deficient CD8 T cells retrovirally overexpressing cMyc or AP4

Project description:To determine functional overlap between cMyc and AP4 in CD8+ T cell priming, we retrovirally expressed cMyc or AP4 in cMyc-deficient CD8+ T cells and examined gene expression after activation. Naive CD8+ T cells from Myc conditional knockout mice with a tamoxifen inducible Cre transgene were retrovirally transduced with Myc or AP4 followed by a treatment with 4-hydroxytamoxifen in the presence of IL-7 for 2 days. RNA was harvested 48 hours after restimulation of transduced cells with anti-CD3 antibody and gene expression was compared by microarray. CD8+ T cells from littermate wildtype mice that were transduced with an empty retrovirus were used as control.

2014-07-13 | E-GEOD-58079 | biostudies-arrayexpress

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