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| Status |
Public on Nov 17, 2018 |
| Title |
STAT3 binding to DNA in wildtype vs B cell specific STAT3 knockout mice |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
A mutation in the Signal Transducer and Activator of Transcription 3 (STAT3) has been linked to incidence of Autosomal Dominant Hyper Immunoglobulin E Syndrome (AD-HIES), a disease characterized by elevated serum IgE antibody. However, how this genetic mutation leads to the phenotype has not been fully understood. We investigated the specific role of STAT3 in the germinal center (GC) B cells and plasma cells for IgE class switching. Through the use of STAT3 conditional knockout mice in a Th2-type immunization model, we demonstrated that CD2-Cre driven STAT3 cKO mice showed elevated IgE and decreased IgG1 in the serum, and a reduction in GC formation. Within the GC, IgG1+ GC B cells were decreased while IgE+ GC B cells were more prevalent. Additionally, these mice exhibited reduced IgG1 and elevated IgE populations of antibody-producing plasma cells. Subsequent experiments using a CD19-Cre B-cell specific cKO mouse established this effect to be B-cell intrinsic. Transcription factors critical for GC and plasma cell differentiation, including Bcl-6 and Aicda, were shown to function as downstream signals of STAT3 regulation. Further ChIP-seq analysis revealed that many genes including Bcl3 and Crtc2 were among the direct STAT3 regulated targets. Mice with STAT3 deficiency in B cells also demonstrated an increase in lung inflammation when used in an asthma-like disease model. This model suggests a negative role for STAT3 in regulating class switching of the GC B cells from the IgG1 to the IgE producing state, which may serve as a therapeutic target for treatment of AD-HIES and other immune disorders.
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| Overall design |
Chip-seq peaks from two biological replicates of STAT3 knockout mouse DNA were compared to the ChIP-Seq peaks from wild type mouse DNA
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| Contributor(s) |
Dascani P, Ding C, Kong X, Tieri D, Hu X, Zhang H, Daisuke K, Bolli R, Rouchka EC, Yan J |
| Citation(s) |
31026806 |
| Submission date |
Sep 17, 2018 |
| Last update date |
May 16, 2019 |
| Contact name |
Eric Christian Rouchka |
| E-mail(s) |
eric.rouchka@louisville.edu
|
| Organization name |
University of Louisville
|
| Department |
Biochemistry and Molecular Genetics
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| Lab |
KY INBRE Bioinformatics Core
|
| Street address |
522 East Gray Street
|
| City |
Louisville |
| State/province |
Kentucky |
| ZIP/Postal code |
40292 |
| Country |
USA |
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| Platforms (1) |
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| Samples (5)
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| Relations |
| BioProject |
PRJNA491411 |
| SRA |
SRP161882 |
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