OBF1 and Oct factors control the germinal center transcriptional program
| Autor: | Michael B. Stadler, Gerhard Christofori, Fabian Wu, Chun Cao, Stefan Dirnhofer, Stephen L. Nutt, Fengyuan Tang, Mathias Frederiksen, Patrick Matthias, Hubertus Kohler, Barna D. Fodor, Simon N. Willis, Mohamed-Amin Choukrallah, Shuang Song, Jacob T. Jackson |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Chromatin Immunoprecipitation Transcription Genetic Immunology Mice Transgenic Biology Biochemistry Proto-Oncogene Protein c-ets-1 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor Coactivator Animals Humans RNA Small Interfering Enhancer Transcription factor B-Lymphocytes POU domain Lymphoma Non-Hodgkin Germinal center Promoter Cell Biology Hematology BCL6 Germinal Center Recombinant Proteins Cell biology Chromatin Mice Inbred C57BL 030104 developmental biology Gene Ontology HEK293 Cells 030220 oncology & carcinogenesis Trans-Activators RNA Interference Octamer Transcription Factor-2 Octamer Transcription Factor-1 |
| Zdroj: | Blood. 137(21) |
| ISSN: | 1528-0020 |
| Popis: | OBF1 is a specific coactivator of the POU family transcription factors OCT1 and OCT2. OBF1 and OCT2 are B cell–specific and indispensable for germinal center (GC) formation, but their mechanism of action is unclear. Here, we show by chromatin immunoprecipitation-sequencing that OBF1 extensively colocalizes with OCT1 and OCT2. We found that these factors also often colocalize with transcription factors of the ETS family. Furthermore, we showed that OBF1, OCT2, and OCT1 bind widely to the promoters or enhancers of genes involved in GC formation in mouse and human GC B cells. Short hairpin RNA knockdown experiments demonstrated that OCT1, OCT2, and OBF1 regulate each other and are essential for proliferation of GC-derived lymphoma cell lines. OBF1 downregulation disrupts the GC transcriptional program: genes involved in GC maintenance, such as BCL6, are downregulated, whereas genes related to exit from the GC program, such as IRF4, are upregulated. Ectopic expression of BCL6 does not restore the proliferation of GC-derived lymphoma cells depleted of OBF1 unless IRF4 is also depleted, indicating that OBF1 controls an essential regulatory node in GC differentiation. |
| Databáze: | OpenAIRE |
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