RUNX1 regulates a transcription program that affects the dynamics of cell cycle entry of naive resting B cells
| Autor: | Natalia Kunowska, Anne-Marie Moody, Mohammad M. Karimi, Roshni de Souza, Chad Whilding, Alexis R. Barr, Greg Crawford, Pierangela Sabbattini, Niall Dillon, Inesa Thomsen, Yi-Fang Wang, Jessica Strid, Sanjay Khadayate |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
B-Lymphocytes
CCND2 Gene RBPJ Cell Cycle Immunology breakpoint cluster region Promoter Biology Hematopoiesis Cell biology Immune Regulation Mice Cyclin D2 1107 Immunology hemic and lymphatic diseases Core Binding Factor Alpha 2 Subunit Conditional gene knockout embryonic structures Animals Immunology and Allergy Promoter Regions Genetic Enhancer Transcription factor |
| Zdroj: | The Journal of Immunology Author Choice |
| Popis: | Key Points RUNX1 reduces cell cycle and immediate early gene expression in naive B cells.BCR stimulation triggers a switch from RUNX1 to RUNX3 binding at cell cycle genes.Notch signaling is downregulated by RUNX1 in follicular B cells. RUNX1 is a transcription factor that plays key roles in hematopoietic development and in hematopoiesis and lymphopoiesis. In this article, we report that RUNX1 regulates a gene expression program in naive mouse B cells that affects the dynamics of cell cycle entry in response to stimulation of the BCR. Conditional knockout of Runx1 in mouse resting B cells resulted in accelerated entry into S-phase after BCR engagement. Our results indicate that Runx1 regulates the cyclin D2 (Ccnd2) gene, the immediate early genes Fosl2, Atf3, and Egr2, and the Notch pathway gene Rbpj in mouse B cells, reducing the rate at which transcription of these genes increases after BCR stimulation. RUNX1 interacts with the chromatin remodeler SNF-2–related CREB-binding protein activator protein (SRCAP), recruiting it to promoter and enhancer regions of the Ccnd2 gene. BCR-mediated activation triggers switching between binding of RUNX1 and its paralog RUNX3 and between SRCAP and the switch/SNF remodeling complex member BRG1. Binding of BRG1 is increased at the Ccnd2 and Rbpj promoters in the Runx1 knockout cells after BCR stimulation. We also find that RUNX1 exerts positive or negative effects on a number of genes that affect the activation response of mouse resting B cells. These include Cd22 and Bank1, which act as negative regulators of the BCR, and the IFN receptor subunit gene Ifnar1. The hyperresponsiveness of the Runx1 knockout B cells to BCR stimulation and its role in regulating genes that are associated with immune regulation suggest that RUNX1 could be involved in regulating B cell tolerance. |
| Databáze: | OpenAIRE |
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