Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by excess B and T cell activation, the development of autoantibodies against self-antigens including nuclear antigens, and immune complex deposition in target organs which triggers an inflammatory response and tissue damage. The genetic and environmental factors that contribute to development of SLE have been extensively studied in both humans and mouse models of the disease. One of the important genetic contributions to SLE development is an alteration in the expression of the transcription factor Ets1, which regulates the functional differentiation of lymphocytes. Here we review the genetic, biochemical and immunological studies that have linked low levels of Ets1 to aberrant lymphocyte differentiation and to the pathogenesis of SLE.
BackgroundThe transcription factor Ets1 is highly expressed in B lymphocytes. Loss of Ets1 leads to premature B cell differentiation into antibody-secreting cells (ASCs), secretion of autoantibodies, and development of autoimmune disease. Despite the importance of Ets1 in B cell biology, few Ets1 target genes are known in these cells.ResultsTo obtain a more complete picture of the function of Ets1 in regulating B cell differentiation, we performed Ets1 ChIP-seq in primary mouse B cells to identify >10,000-binding sites, many of which were localized near genes that play important roles in B cell activation and differentiation. Although Ets1 bound to many sites in the genome, it was required for regulation of less than 5% of them as evidenced by gene expression changes in B cells lacking Ets1. The cohort of genes whose expression was altered included numerous genes that have been associated with autoimmune disease susceptibility. We focused our attention on four such Ets1 target genes Ptpn22, Stat4, Egr1, and Prdm1 to assess how they might contribute to Ets1 function in limiting ASC formation. We found that dysregulation of these particular targets cannot explain altered ASC differentiation in the absence of Ets1.ConclusionWe have identified genome-wide binding targets for Ets1 in B cells and determined that a relatively small number of these putative target genes require Ets1 for their normal expression. Interestingly, a cohort of genes associated with autoimmune disease susceptibility is among those that are regulated by Ets1. Identification of the target genes of Ets1 in B cells will help provide a clearer picture of how Ets1 regulates B cell responses and how its loss promotes autoantibody secretion.
Ets1 is a key transcription factor in B cells that is required to prevent premature differentiation into Ab-secreting cells. Previously, we showed that BCR and TLR signaling downregulate Ets1 levels and that the kinases PI3K, Btk, IKK, and JNK are required for this process. PI3K is important in activating Btk by generating the membrane lipid phosphatidylinositol (3,4,5)-trisphosphate, to which Btk binds via its PH domain. Btk in turn is important in activating the IKK kinase pathway, which it does by activating phospholipase Cγ2→protein kinase Cβ signaling. In this study, we have further investigated the pathways regulating Ets1 in mouse B cells. Although IKK is well known for its role in activating the canonical NF-κB pathway, IKK-mediated downregulation of Ets1 does not require either RelA or c-Rel. We also examined the potential roles of two other IKK targets that are not part of the NF-κB signaling pathway, Foxo3a and mTORC2, in regulating Ets1. We find that loss of Foxo3a or inhibition of mTORC2 does not block BCR-induced Ets1 downregulation. Therefore, these two pathways are not key IKK targets, implicating other as yet undefined IKK targets to play a role in this process.
The transcription factor (TF) Ets1 plays a critical role in maintaining B cell quiescence. High Ets1 levels in resting B cells prevent premature plasma cell differentiation and suppress autoimmune responses, but Ets1 must be downregulated to allow for proper B cell responses. Despite this vital role, it remains unknown how the Ets1 expression pattern is coordinated. Upon activation of antigen receptors (ARs), Ets1 is downregulated and quantification of newly transcribed pre-mRNA indicates that a decrease in Ets1 gene transcription is responsible. New protein synthesis is shown to be dispensable for this downregulation, suggesting that it does not rely on upregulation of a repressor but rather changes in abundance or activity of existing TFs. NFκB is activated in response to AR signaling and its binding motifs are found in putative regulatory elements identified near the Ets1 gene. Inhibition of NFκB-activating kinase IKK2 prevents the decrease in Ets1 transcription in response to AR stimulation. However, neither RelA nor cRel downstream of IKK2 are required for proper control of Ets1 expression. Next, we examined potential roles for Foxo3 and Rictor, unconventional downstream effectors of IKK2. Foxo3 has a similar expression pattern to Ets1 and is downregulated upon BCR stimulation, but B cells lacking Foxo3 regulate Ets1 expression in a manner similar to WT B cells. Rictor is a component of the mTORC2 complex, but inhibition of mTOR signaling does not impact Ets1 downregulation in response to BCR stimulation. Overall, these data suggest that Ets1 expression is coordinated by unconventional, but as of yet unidentified, downstream effectors of IKK2 in response to AR signaling. Funded by NIH R01 AI122720 and the Lupus Research Alliance.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.