Identifying Ets1 Target Genes in Human B Cells
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Ets1 is a transcription factor that is highly expressed in B cells and regulates their functions. Ets1 deficiency leads to impaired B cell tolerance to self-antigens and auto-antibody production that causes autoimmune disorders. The human Ets1 gene has also been identified as a susceptibility locus for lupus and other autoimmune diseases. Our lab has studied the roles of Ets1 in preventing excess B cell activation and autoantibody secretion using mouse models. However, very little has done to understand the role of Ets1 in human B cells. In this study, 41 Ets1 target genes were identified using RNA-sequencing in a human B cell line where Ets1 was knocked down. This is a substantially smaller cohort of genes whose expression changes in human B cells in the absence of Ets1 when compared with changed genes expression in mouse B cells lacking Ets1. Despite, the small number, the genes identified were interesting candidates for regulating human B cell differentiation. Six genes were upregulated and 35 genes were downregulated in the absence of Ets1. Pathway analysis showed that upregulated genes in the absence of Ets1 were associated with nuclear and alternative splicing functions, while downregulated genes were linked to GTPase signaling and cell adhesion and migration. Changes in gene expression were validated for four selected genes using qPCR assays. ChIP-seq data on Ets1 from the same human cell line, showed that some of the genes whose expression changed in the absence of Ets1 have a nearby Ets1 binding peak, suggesting they are direct targets of Ets1 activity. In this study, a cohort of target genes was identified and may contribute to the mechanisms used by Ets1 to regulate human B cell differentiation. These gene targets may be important for understanding how Ets1 prevents inappropriate B cell activation and prevents autoimmune disease from developing.