RUNX1 controls the dynamics of cell cycle entry of naive resting B cells by regulating expression of cell cycle and immunomodulatory genes in response to BCR stimulation

Abstract

RUNX1 is a transcription factor that plays key roles in haematopoietic development and in adult haematopoiesis and lymphopoiesis. Here we report that RUNX1 is also involved in controlling the dynamics of cell cycle entry of naive resting B cells in response to stimulation of the B cell receptor (BCR). Conditional knockout of Runx1 in mouse resting B cells resulted in accelerated entry of the cells into S-phase following BCR engagement. Our results indicate that Runx1 regulates the cyclin D2 (Ccnd2) gene, the immediate early genes, Fosl2, Atf3 and Egr2, and the Notch effector Rbpj, in B cells, reducing the rate at which transcription of these genes increases following BCR stimulation. RUNX1 interacts with the chromatin remodeller 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 SWI/SNF remodelling complex member BRG1. We also find that RUNX1 regulates expression of a number of immunomodulatory genes in resting B cells. These include the interferon receptor subunit gene Ifnar1, which is upregulated in B cells from lupus patients, the Ptpn22 gene, which has been identified as a major lupus risk allele, and the Lrrk2 gene, which is mutated in familial Parkinsons disease. The hyperresponsiveness of the Runx1 knockout B cells to antigen stimulation and its role in regulating a suite of genes that are known to be associated with autoimmune disease suggest that RUNX1 is a major regulator of B cell tolerance and autoimmunity.